C3-carbon linked glutarimide degronimers for target protein degradation

ABSTRACT

This invention provides Degronimers that have carbon-linked E3 Ubiquitin Ligase targeting moieties (Degrons), which can be linked to a targeting ligand for a protein that has been selected for in vivo degradation, and methods of use and compositions thereof as well as methods for their preparation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2017/032041, filed in the International Patent Cooperation Treaty,U.S. Receiving Office on May 10, 2017, which claims the benefit ofpriority to U.S. Application No. 62/334,362, filed May 10, 2016. Theentirety of these applications are hereby incorporated by referenceherein for all purposes.

FIELD OF THE INVENTION

This invention provides Degronimers that have carbon-linked E3 UbiquitinLigase targeting moieties (Degrons), which can be linked to a targetingligand for a protein that has been selected for in vivo degradation, andmethods of use and compositions thereof as well as methods for theirpreparation.

BACKGROUND

Protein degradation is a highly regulated and essential process thatmaintains cellular homeostasis. The selective identification and removalof damaged, misfolded, or excess proteins is achieved via theubiquitin-proteasome pathway (UPP). The UPP is central to the regulationof almost all cellular processes, including antigen processing,apoptosis, biogenesis of organelles, cell cycling, DNA transcription andrepair, differentiation and development, immune response andinflammation, neural and muscular degeneration, morphogenesis of neuralnetworks, modulation of cell surface receptors, ion channels and thesecretory pathway, the response to stress and extracellular modulators,ribosome biogenesis and viral infection.

Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitinligase to a terminal lysine residue marks the protein for proteasomedegradation, where the protein is digested into small peptides andeventually into its constituent amino acids that serve as buildingblocks for new proteins. Defective proteasomal degradation has beenlinked to a variety of clinical disorders including Alzheimer's disease,Parkinson's disease, Huntington's disease, muscular dystrophies,cardiovascular disease, and cancer among others.

There are over 600 E3 ubiquitin ligases which facilitate theubiquitination of different proteins in vivo, which can be divided intofour families: HECT-domain E3s, U-box E3s, monomeric RING E3s andmulti-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487)titled “Genome-wide and functional annotation of human E3 ubiquitinligases identifies MULAN, a mitochondrial E3 that regulates theorganelle's dynamics and signaling.”; Berndsen et al. (Nat. Struct. Mol.Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligasemechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434)titled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem.2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures,new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014,14, 233-347) titled “Roles of F-box proteins in cancer.”

In 1995, Gosink et al. (Proc. Natl. Acad. Sci. USA 1995, 92, 9117-9121)in a publication titled “Redirecting the Specificity of Ubiquitinationby Modifying Ubiquitin-Conjugating Enzymes”, provided proof of conceptin vitro that engineered peptides can selectively direct ubiquitinationof intracellular proteins. The publication by Nawaz et al. (Proc. Natl.Acad. Sci. U.S.A. 1999, 96, 1858-1862) titled “Proteasome-DependentDegradation of the Human Estrogen Receptor” describes ER degradationwhich takes advantage of the ubiquitin-proteasome pathway.

Proteinex, Inc. filed a patent application in February 1999 that issuedas U.S. Pat. No. 6,306,663 claiming a method of generating a compoundfor activating the ubiquitination of a Target Protein which comprisescovalently linking a Target Protein binding element able to bindspecifically to the Target Protein via a ubiquitination recognitionelement. Proteinex described that the invention can be used to controlprotein levels in eukaryotes. While the '663 patent may have been basedon the first patent application to describe the high level concept ofhow to manipulate the UPP system to degrade selected proteins in vivo,the patent did not provide sufficient detail to allow persons of skillto easily construct the range of proposed compounds. For example, forthe ubiquitination recognition elements, the skilled person was toldamong other things to use standard methods for drug discovery and screenfor appropriate small molecules that would bind to the ligase. Proteinexalso emphasized the use of peptides as ubiquitination recognitionelements, which can pose significant difficulties for oral drugadministration.

Since then, harnessing the ubiquitin-proteasome pathway for therapeuticintervention has received significant interest from the scientificcommunity. The publication by Zhou et al. from Harvard Medical School(Mol. Cell 2000, 6, 751-756) titled “Harnessing the UbiquitinationMachinery to Target the Degradation of Specific Cellular Proteins”described an engineered receptor capable of directing ubiquitination inmammalian and yeast cells.

Following from these early publications and others in the mid to late1990s, the work of Proteinex was confirmed by Craig Crews and coworkers(Yale University) that a molecule that is capable of binding a TargetProtein and a ubiquitin ligase may cause the Target Protein to bedegraded. Their first description of such compounds was provided in U.S.Pat. No. 7,041,298 filed in September 2000 by Deshaies et al. andgranted in May 2006 titled “Proteolysis Targeting ChimericPharmaceutical”, which described a “PROTAC” consisting of a smallmolecule binder of MAP-AP-2 linked to a peptide capable of binding theF-box protein □-TRCP. Information in the '298 patent is also presentedin the corresponding publication by Sakamoto et al. (Proc. Natl. Acad.Sci. USA 2001, 98, 8554-8559) titled “Protacs: Chimeric Molecules ThatTarget Proteins to the Skp1-Cullin-F Box Complex for Ubiquitination andDegradation”. The publication by Sakamoto et al. (Mol. Cell. Proteomics2003, 2, 1350-1358) titled “Development of Protacs to TargetCancer-Promoting Proteins for Ubiquitination and Degradation” describesan analogous PROTAC (PROTAC2) that instead of degrading MAP-AP-2degrades estrogen and androgen receptors.

The first E3 ligase successfully targeted with a small molecule wasMDM2, which ubiquitinates the tumor suppressor p53. The targeting ligandwas an HDM2/MDM2 inhibitor identified in Vassilev et al. (Science 2004,303, 844-848) titled “In Vivo Activation of the P53 Pathway bySmall-Molecule Antagonists of MDM2”.

Other examples of direct small molecule-induced recruitment of TargetProteins to the proteasome for degradation on addition to cultured cellswere described in 2004 (Schneekloth et al. (J. Am. Chem. Soc. 2004, 126,3748-3754) titled “Chemical Genetic Control of Protein Levels: Selectivein Vivo Targeted Degradation”). Schneekloth et al. describe adegradation agent (PROTAC3) that targets the FK506 binding protein(FKBP12) and shows that both PROTAC2 and PROTAC3 hit their respectivetargets with green fluorescent protein (GFP) imaging. The publication bySchneekloth et al. (Chem Bio Chem 2005, 6, 40-46) titled “ChemicalApproaches to Controlling Intracellular Protein Degradation” describedthe state of the field at the time.

The publication by Schneekloth et al. (Bioorg. Med. Chem. Lett. 2008,18, 5904-5908) titled “Targeted Intracellular Protein DegradationInduced by a Small Molecule: En Route to Chemical Proteomics” describesa degradation agent that consists of two small molecules linked by PEGthat in vivo degrades the androgen receptor by concurrently binding theandrogen receptor and ubiquitin E3 ligase.

WO 2013/170147 filed by Crews et al. titled “Compounds Useful forPromoting Protein Degradation and Methods of Using Same” describescompounds comprising a protein degradation moiety covalently bound to alinker, wherein the ClogP of the compound is equal to or higher than1.5. In particular, the specification discloses protein degradingcompounds that incorporate certain small molecules that can bind to anE3 ubiquitin ligase.

In unrelated parallel research, scientists were investigatingthalidomide toxicity. Ito et al. (Science 2010, 327, 1345-1350) titled“Identification of a Primary Target of Thalidomide Teratogenicity”,described that cereblon is a thalidomide binding protein. Cereblon formspart of an E3 ubiquitin ligase protein complex which interacts withdamaged DNA binding protein 1, forming an E3 ubiquitin ligase complexwith Cullin 4 and the E2-binding protein ROC1 (also known as RBX1) whereit functions as a substrate receptor to select proteins forubiquitination. The study revealed that thalidomide-cereblon binding invivo may be responsible for thalidomide teratogenicity. After thediscovery that thalidomide causes teratogenicity in the mid-1960's, thecompound and related structures were notwithstanding found to be usefulas anti-inflammatory, anti-angiogenic and anti-cancer agents (seeBartlett et al. (Nat. Rev. Cancer 2004, 4, 314-322) titled “TheEvolution of Thalidomide and Its Imid Derivatives as AnticancerAgents”).

The disclosure that thalidomide binds to the cereblon E3 ubiquitinligase led to research to investigate incorporating thalidomide andcertain derivatives into compounds for the targeted destruction ofproteins. Two seminal papers were published in Science in 2014: G. Lu etal., The Myeloma Drug Lenalidomide Promotes the Cereblon-DependentDestruction of Ikaros Proteins, Science, 343, 305-309 (2014); and J.Kronke et al., Lenalidomide Causes Selective Degradation of IKZF1 andIKZF3 in Multiple Myeloma Cells, Science, 343, 301-305 (2014).

U.S. 2014/0356322 assigned to Yale University, GlaxoSmithKline, andCambridge Enterprise Limited University of Cambridge titled “Compoundsand Methods for the Enhanced Degradation of Target Proteins & OtherPolypeptides by an E3 Ubiquitin Ligase” describes protein degradingcompounds that bind to the VHL E3 Ubiquitin Ligase. See also Buckley etal. (J. Am. Chem. Soc. 2012, 134, 4465-4468) titled “Targeting the VonHippel-Lindau E3 Ubiquitin Ligase Using Small Molecules to Disrupt theVhl/Hif-1alpha Interaction”.

Additional publications in this area include the following: Lu et al.(Chem. Biol. 2015, 22, 755-763) titled “Hijacking the E3 UbiquitinLigase Cereblon to Efficiently Target Brd4”; Bondeson et al. (Nat. Chem.Biol. 2015, 11, 611-617) titled “Catalytic in Vivo Protein Knockdown bySmall-Molecule Protacs”; Gustafson et al. (Angewandte Chemie,International Edition in English 2015, 54, 9659-9662) titled“Small-Molecule-Mediated Degradation of the Androgen Receptor throughHydrophobic Tagging”; Lai et al. (Angewandte Chemie, InternationalEdition in English 2016, 55, 807-810) titled “Modular Protac Design forthe Degradation of Oncogenic Bcr-Abl”; Toure et al. (Angew. Chem. Int.Ed. 2016, 55, 1966-1973) titled “Small-Molecule Protacs: New Approachesto Protein Degradation”; and Winter et al. (Science 2015, 348,1376-1381) titled “Drug Development. Phthalimide Conjugation as aStrategy for in Vivo Target Protein Degradation” describes thalidomidebased Target Protein degradation technology.

WO 2015/160845 assigned to Arvinas Inc. titled “Imide Based Modulatorsof Proteolysis and Associated Methods of Use” describes proteindegradation compounds that incorporate thalidomide and certainderivatives which bind to a cereblon E3 ligase. Additional patentapplications filed by Arvinas Inc. directed to the degradation of aTarget Protein using known E3 ligase ligands to direct the TargetProtein to the proteasome for degradation include U.S. 2016/0058872titled “Imide Based Modulators of Proteolysis and Associated Methods ofUse”; U.S. 2016/0045607 titled “Estrogen-related Receptor Alpha BasedPROTAC Compounds and Associated Methods of Use”; U.S. 2016/0214972titled “Compounds and Methods for the Targeted Degradation of AndrogenReceptor”; U.S. 2016/0272639 titled “Compounds and Methods for theEnhanced Degradation of Target Proteins”; U.S. 2017/0008904 titled“MDM2-Based Modulators of Proteolysis and Associated Methods of Use”;U.S. 2017/0037004 titled “Alanine-Based Modulators of Proteolysis andAssociated Methods of Use”; U.S. 2017/0065719 titled “Compounds andMethods for the Targeted Degradation of Bromodomain containingproteins”; WO 2016/036036 titled “Tank Binding Kinase-1 PROTACS andAssociated Methods of Use”; and WO 2016/197032 “Imide-Based Modulatorsand Proteolysis and Associated Methods of Use”.

Dana-Farber Cancer Institute has also filed several patent applicationsdirected to the degradation of a Target Protein using known E3 ligaseligands to direct the Target Protein to the proteasome for degradation.These filings include US 2016/0176916 titled “Methods to Induce TargetProtein Degradation through Bifunctional Molecules; WO 2017/024318titled “Target Protein Degradation to Attenuate Adoptive T-Cell TherapyAssociated Adverse Inflammatory Responses”; WO 2017/024317 titled“Methods to Induce Target Protein Degradation through BifunctionalMolecules”; and WO 2017/024319 titled “Tunable Endogenous ProteinDegradation”.

While progress has been made in the area of modulation of the UPP for invivo protein degradation, it would be useful to have additionalcompounds and approaches to more fully harness the UPP for therapeutictreatments.

It is an object of the present invention to provide new compounds,methods, compositions, and methods of manufacture that are useful todegrade selected proteins in vivo.

SUMMARY

Compounds and their uses and manufacture are provided that causedegradation of a selected protein via the ubiquitin proteasome pathway(UPP). It has been surprisingly discovered that C³-carbonsubstituted-glutarimides and analogues thereof described herein(Degrons) bind an E3 ligase (typically the cereblon protein).Degronimers are disclosed of Formulas I, IL, V and VI that include a“Targeting Ligand” that binds (typically non-covalently) to a selectedTarget Protein, a “Degron” which binds (typically non-covalently) to anE3 Ligase (typically via cereblon) and optionally a Linker thatcovalently links the Targeting Ligand to the Degron.

A Degronimer provided herein or its pharmaceutically acceptable saltand/or its pharmaceutically acceptable composition can be used to treata disorder which is mediated by the selected Target Protein that bindsto the Targeting Ligand. Therefore, in some embodiments a method totreat a host with a disorder mediated by the Target Protein is providedthat includes administering an effective amount of the Degronimer or itspharmaceutically acceptable salt described herein to the host, typicallya human, optionally in a pharmaceutically acceptable composition.

In one embodiment, the selected Target Protein is derived from a genethat has undergone an amplification, translocation, deletion, orinversion event which causes or is caused by a medical disorder. Incertain aspects, the selected Target Protein has beenpost-translationally modified by one, or combinations, ofphosphorylation, acetylation, acylation including propionylation andcrotylation, N-linked glycosylation, amidation, hydroxylation,methylation, poly-methylation, O-linked glycosylation,pyroglutamoylation, myristoylation, farnesylation, geranylation,ubiquitination, sumoylation, or sulfation which causes or is caused by amedical disorder. In an alternative embodiment, the Target Protein canbe covalently modified by a Targeting Ligand that has beenfunctionalized to create a covalent bond with the Target Protein, andthe covalently bond can be irreversible or reversible.

In one aspect of the present invention a Degronimer of Formula I orFormula II is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition;wherein:

-   -   W¹ is CR¹R², C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,        P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;    -   W² is CR³R⁴, C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,        P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;    -   in a typical embodiment W¹ is C═O;    -   in another typical embodiment W² is C═O;    -   X is independently selected from NH, NR¹², CH₂, CHR¹², C(R¹²)₂,        O, or S;    -   n is 0, 1, 2, or 3;    -   is a single or double bond;

R⁶ is selected from:

or R⁶ is selected from:

or R⁶ is selected from:

or R⁶ is selected from:

or R⁶ is selected from:

Y is independently selected from N, CH, and CR¹¹, wherein 0, 1, 2, 3, or4 (as context allows) instances of Y are selected to be N and isselected to produce a stable ring and a pharmaceutically acceptableDegronimer. When Y's are in a six-membered ring (unfused or fused), thering can be, in non-limiting embodiments as allowed by context, apyridine, diazine, triazine, pyrimidine, pyridazine, pyrazine, triazineor tetrazine.

Z is NH, O, S, or NR¹²;

Z² is NH or NR¹²;

When Y and/or Y and Z are in a 5-membered ring there is typically notmore than 1, 2, 3, or 4 heteroatoms, and non-limiting examples arepyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole,thiazole, isothiazole, triazole, furazan, oxadiazole, thiadiazole,diazole and tetrazole.

and when R¹⁰ is bonded to a Y that is carbon, then Y is CR¹⁰, and whenR¹⁰ is bonded to a Z or Z² that is nitrogen, then Z or Z² is NR¹⁰, etc.

R¹, R², R³, R⁴, R⁷, R⁸, and R¹⁵ are independently selected fromhydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, carbocyclic,aryl, heteroaryl, hydroxyl, halo, azide, CN—, alkoxy, amine, —NHalkyl,and —Nalkyl₂, —NH(aliphatic), and —N(independently aliphatic)₂, each ofwhich may be optionally substituted as described in the DefinitionSection, if desired to achieve the target effect, results in a stablecompound that makes chemical sense to the routineer, and the group isnot redundant (i.e., as known in the art, alkyl substituted with alkylis redundant; however for examples, alkoxy substituted with alkoxy isnot redundant);

or R¹ and R² together with the carbon to which they are attached form a3-, 4-, 5-, or 6-membered spiro-carbocycle, or a 4-, 5-, or 6-memberedspiro-heterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R³ and R⁴ together with the carbon to which they are attached form a3-, 4-, 5-, or 6-membered spiro-carbocycle, or a 4-, 5-, or 6-memberedspiro-heterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R⁷ and R⁸ together with the carbon to which they are attached form a3-, 4-, 5-, or 6-membered spiro-carbocycle, or a 4-, 5-, or 6-memberedspiro-heterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R¹ and R³ form a 1 or 2 carbon bridged ring;

or R¹ and R⁷ form a 1 or 2 carbon bridged ring;

or R³ and R⁷ form a 1 or 2 carbon bridged ring;

or R¹⁵ and R¹ form a 3, 4, 5, or 6 carbon fused ring;

or R¹⁵ and R⁷ form a 3, 4, 5, or 6 carbon fused ring;

or R¹⁵ and R³ form a 1 or 2 carbon bridged ring;

or R¹⁵ and R⁵ form a 3, 4, 5, or 6 carbon fused ring wherein R⁵ is onthe carbon alpha to R¹⁵ or a 1, 2, 3, or 4 carbon bridged ring whereinR⁵ is not on the carbon alpha to R¹⁵;

R⁵ is selected at each instance from: alkyl, alkene, alkyne, aliphatic,heteroaliphatic, heterocyclic, aryl, heteroaryl, halogen, hydroxyl,alkoxy, azide, amino, —NH(alkyl or aliphatic), —N(independently alkyl oraliphatic)₂, —NHSO₂(aliphatic, including alkyl), —N(alkyl oraliphatic)SO₂(alkyl or aliphatic), —NHSO₂aryl, —N(alkyl oraliphatic)SO₂aryl, —NHSO₂alkenyl, —N(alkyl or aliphatic)SO₂alkenyl,—NHSO₂alkynyl, —N(alkyl or aliphatic)SO₂alkynyl, and halo(alkyl oraliphatic), each of which is provided to form a stable compound as knownto those of skill in the art, and can be optionally substituted asdescribed in the Definition Section, if desired to achieve the targeteffect, results in a stable compound that makes chemical sense to theroutineer, and the group is not redundant (i.e., as known in the art,alkyl substituted with alkyl is redundant; however for examples, alkoxysubstituted with alkoxy is not redundant);

or two R⁵ substituents together with the carbon atom(s) to which theyare bound can form a 3, 4, 5 or 6 membered ring;

R¹⁰ is -Linker-Targeting Ligand;

R¹¹ is selected at each instance from: hydrogen, alkyl, alkenyl,alkynyl, halogen, hydroxyl, heterocyclic, heteroalkyl, carbocyclic,heteroaliphatic, aliphatic, alkoxy, aryl, heteroaryl, alkylamino,alkylhydroxyl, —NHalkyl, —Nalkyl₂, —NH(aliphatic), —N(independentlyaliphatic)₂, amino, cyano, nitro, nitroso, sulfone, sulfoxide,thioalkyl, thiol and haloalkyl, each of which is optionally substitutedas described in the Definition Section, if desired to achieve the targeteffect, results in a stable compound that makes chemical sense to theroutineer;

R¹² is selected at each instance from: hydrogen, alkyl, aliphatic,heteroaliphatic, heterocyclic, heteroaryl, aryl, —C(O)H, —C(O)OH,—C(O)alkyl, —C(O)Oalkyl, —C(O)(aliphatic, aryl, heteroaliphatic, aryl orheteroaryl), —C(O)O(aliphatic, aryl, heteroaliphatic, aryl orheteroaryl), alkene, and alkyne, each of which is optionally substitutedas described in the Definition Section, if desired to achieve the targeteffect, results in a stable compound that makes chemical sense to theroutineer;

R¹³ and R¹⁴ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, alkoxy, haloalkoxy, hydroxy, amino, —NHalkyl, and —N(alkyl)₂,each of which is optionally substituted as described in the DefinitionSection, if desired to achieve the target effect, results in a stablecompound that makes chemical sense to the routineer; and

or R¹³ and R¹⁴ together with the carbon atom to which they are attached,form C(O), C(S), C═CH₂, a 3-, 4-, 5-, or 6-membered spirocarbocycle, ora 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatomsselected from N and O.

Formula V provides further Degronimers of the present invention:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition; wherein the R moieities are as described above.

Formula VII provides additional Degronimers of the present invention:

wherein:

R¹⁷ is selected from:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition; wherein the R moieties are as described above.

Linker is a chemical group that attaches the Degron to a TargetingLigand, as described further below.

Targeting Ligand is a small molecule or moiety (for example a peptide,nucleotide, antibody, antibody fragment, aptamer, biomolecule or otherchemical structure) that binds to a Target Protein, and wherein theTarget Protein is a mediator of disease in a host as described in detailbelow.

In any of the fused rings that have an R¹⁰, the R¹⁰ can be placed on anyavailable ring atom on either of the fused rings, except when excludedby context (such as where valency precludes), for example, as shown inthe formulas:

includes compounds of structure

and each is considered specifically and independently described.

The structure of the Degronimer is typically selected such that it issufficiently stable to sustain a shelf life of at least two, three,four, or five months under ambient conditions. To accomplish this, eachof the R groups described herein must be sufficiently stable to sustainthe corresponding desired shelf life of at least two, three, four orfive months under ambient conditions.

Degronimers of Formula I, II, V and VII are bifunctional with novelcarbon-linked E3 Ubiquitin Ligase targeting moieties (Degrons) linked toTargeting Ligands (described in more detail below), which function torecruit Target Proteins to E3 Ubiquitin Ligase, typically throughcereblon, for degradation. One non-limiting example of a disordertreatable by such compounds is abnormal cellular proliferation, such asa tumor or cancer, wherein the Target Protein is an oncogenic protein ora signaling mediator of an abnormal cellular proliferative pathway andits degradation decreases abnormal cell growth.

Based on this discovery, compounds and methods are presented for thetreatment of a patient with a disorder mediated by a protein that istargeted for selective degradation that includes administering aneffective amount of one or a combination of the Degronimers of FormulaI, Formula II, Formula V or Formula VII or a pharmaceutically acceptablesalt thereof, as described herein to a patient (typically a human) inneed thereof, optionally in a pharmaceutically acceptable carrier. Incertain embodiments the disorder is selected from a benign growth,neoplasm, tumor, cancer, abnormal cellular proliferation, immunedisorder, autoimmune disorder, inflammatory disorder, graft-versus-hostrejection, infectious disease, viral infection, bacterial infection, anamyloid-based proteinopathy, a proteinopathy, or fibrotic disorder. In atypical embodiment the patient is a human.

In one embodiment, the present invention provides carbon-linked moietieswhich are covalently linked to a Targeted Ligand through a Linker whichcan be of varying length, structure and functionality, as described inmore detail below. In one embodiment, the carbon-linked Degron moiety islinked directly to the Targeting Ligand (i.e., the Linker is a bond). Incertain embodiments, the Linker can be any chemically stable group thatattaches the carbon-linked Degron to the Targeting Ligand.

In one embodiment, the Target Protein is a protein that is not druggablein the classic sense in that it does not have a binding pocket or anactive site that can be inhibited or otherwise bound, and cannot beeasily allosterically controlled. In another embodiment, the TargetProtein is a protein that is druggable in the classic sense. Examples ofTarget Proteins are provided below.

In an alternative embodiment, a carbon-linked C³-glutarimide Degron ofFormula III, IV, or VI as described herein can be used alone (i.e., notas part of a Degronimer) as an in vivo binder of cereblon, which can beadministered to a host, for example, a human, in need thereof, in aneffective amount, optionally as a pharmaceutically acceptable salt, andoptionally in a pharmaceutically acceptable composition, for anytherapeutic indication which can be treated by modulating the functionand or activity of the cereblon-containing E3 Ubiquitin Ligase ProteinComplex, including but not limited to uses known for the cereblonbinders thalidomide, pomalidomide or lenalidomide. In certainalternative embodiments, the compound of Formula III, IV or VI canactivate, decrease or change the natural activity of cereblon.Nonlimiting examples of uses for cereblon binders are multiple myeloma,a hematological disorder such as myelodysplastic syndrome, cancer,tumors, abnormal cellular proliferation, HIV/AIDS, Crohn's disease,sarcoidosis, graft-versus-host disease, rheumatoid arthritis, Behcet'sdisease, tuberculosis, and myelofibrosis.

Thus, in another aspect of the present invention a Degron of Formula IIIor Formula IV is provided of the structure:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition;wherein the R moieties are as defined above and

R¹⁶ is selected from:

In one aspect of the present invention a Degron of Formula VI isprovided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition, wherein the R moieties are as defined above.

Compounds of the present application may offer important clinicalbenefits to patients, in particular for the treatment of the diseasestates and conditions modulated by the proteins of interest.

In certain embodiments, the present invention provides theadministration of an effective amount of a compound of Formula I, II,III, IV, V, VI or VII to treat a patient, for example, a human, havingan infectious disease, wherein the therapy targets a Target Protein ofthe infectious agent or a Target Protein of the host (Formula I, II, Vor VII), or acts via binding to cereblon or its E3 ligase (Formula III,IV or VI) optionally in combination with another bioactive agent. Thedisease state or condition may be caused by a microbial agent or otherexogenous agent such as a virus (as non-limiting examples, HIV, HBV,HCV, HSV, HPV, RSV, CMV, Ebola, Flavivirus, Pestivirus, Rotavirus,Influenza, Coronavirus, EBV, viral pneumonia, drug-resistant viruses,Bird flu, RNA virus, DNA virus, adenovirus, poxvirus, Picornavirus,Togavirus, Orthomyxovirus, Retrovirus or Hepadnovirus), bacteria(including but not limited to Gram-negative, Gram-positive, Atypical,Staphylococcus, Streptococcus, E. Coli, Salmonella, Helicobacter pylori,meningitis, gonorrhea, Chlamydiaceae, Mycoplasmataceae, etc), fungus,protozoa, helminth, worms, prion, parasite, or other microbe.

In certain embodiments, the compound of Formula I, II, III, IV, V, VI orVII has at least one desired isotopic substitution of an atom, at anamount above the natural abundance of the isotope, i.e., enriched. Inone embodiment, the compound of Formula I or Formula II includes adeuterium or multiple deuterium atoms.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this application belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, suitable methods and materials are described below.All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed application. Inthe case of conflict, the present specification, including definitions,will control. In addition, the materials, methods, and examples areillustrative only and are not intended to be limiting.

Other features and advantages of the present invention will be apparentfrom the following detailed description and claims.

The present invention thus includes at least the following features:

(a) A carbon-linked Degronimer of Formula I, II, V or VII as describedherein, and pharmaceutically acceptable salts, isotopic derivative(including a deuterated derivative) and prodrugs thereof;

(b) A carbon-linked Degronimer of Formula I, II, V or VII, for thetreatment of a disorder that is mediated by a Target Protein, whereinthe compound includes a Targeting Ligand for the Target Protein, andwherein the carbon-linked compound is optionally linked to the TargetingLigand through a Linker;

(c) Use of a Degronimer of Formula I, II, V or VII in an effectiveamount in the treatment of a patient, including a human, with a disordermediated by a Target Protein, including abnormal cellular proliferationsuch as a tumor or cancer, an autoimmune disorder or inflammatorydisorder, a cardiac disorder, an infectious disease, or other disorderthat responds to such treatment;

(d) Use of a Degronimer of Formula I or Formula II and pharmaceuticallyacceptable salts, isotopic derivatives and prodrugs thereof in themanufacture of a medicament for the treatment of a medical disorder;

(e) A method for manufacturing a medicament intended for the therapeutictreat a disorder characterized in that a Degronimer of Formula I, II, Vor VII as described herein is used in the manufacture;

(f) A Degronimer of Formula I, II, V or VII as described herein, andpharmaceutically acceptable salts, isotopic derivatives and prodrugsthereof that are useful in the treatment of an abnormal cellularproliferation such as cancer, including any of the cancers describedherein;

(g) Use of a Degronimer of Formula I, II, V or VII and pharmaceuticallyacceptable salts, isotopic derivatives and prodrugs thereof in themanufacture of a medicament for the treatment of an abnormal cellularproliferation such as cancer, including any of the cancers describedherein;

(h) A method for manufacturing a medicament intended for the therapeuticuse of treating an abnormal cellular proliferation such as cancer,including any of the cancers described herein, characterized in that aDegronimer of Formula I, II, V or VII as described herein is used in themanufacture;

(i) A Degronimer of Formula I, II, V or VII as described herein, andpharmaceutically acceptable salts, isotopic derivatives and prodrugsthereof that are useful in the treatment of a tumor, including any ofthe tumors described herein;

(j) Use of a Degronimer of Formula I, II, V or VII and pharmaceuticallyacceptable salts, isotopic derivatives and prodrugs thereof in themanufacture of a medicament for the treatment of a tumor, including anyof the tumors described herein;

(k) A method for manufacturing a medicament intended for the therapeutictreatment of a tumor, including any of the tumors described herein,characterized in that a Degronimer of Formula I, II, V or VII asdescribed herein is used in the manufacture;

(l) A Degronimer of Formula I, II, V or VII as described herein, andpharmaceutically acceptable salts, isotopic derivatives and prodrugsthereof that are useful in the treatment of an immune, autoimmune orinflammatory disorder;

(m) Use of a Degronimer of Formula I, II V or VII and pharmaceuticallyacceptable salts and prodrugs thereof in the manufacture of a medicamentfor the treatment of an immune, autoimmune or inflammatory disorder;

(n) A method for manufacturing a medicament intended for the therapeutictreatment of an immune, autoimmune or inflammatory disorder,characterized in that a Degronimer of Formula I, II, V or VII asdescribed herein is used in the manufacture;

(o) A Degronimer of Formula I, II, V or VII as described herein, andpharmaceutically acceptable salts and prodrugs thereof that are usefulin the treatment of a viral infection, including but not limited to HIV,HBV, HCV and RSV;

(p) Use of a Degronimer of Formula I, II, V or VII, and pharmaceuticallyacceptable salts and prodrugs thereof in the manufacture of a medicamentfor the treatment of a viral infection, including but not limited toHIV, HBV, HCV and RSV;

(q) A method for manufacturing a medicament intended for the therapeutictreatment of a viral infection including but not limited to HIV, HBV,HCV and RSV, characterized in that a Degronimer of Formula I, II, V orVII as described herein is used in the manufacture;

(r) A pharmaceutical formulation comprising an effective host-treatingamount, such as a human-treating amount of the Degronimer of Formula I,II, V or VII or a pharmaceutically acceptable salt or prodrug thereoftogether with a pharmaceutically acceptable carrier or diluent;

(s) A Degronimer of Formula I, II, V or VII as described herein as amixture of enantiomers or diastereomers (as relevant), including as aracemate;

(t) A Degronimer of Formula I, II, V or VII as described herein inenantiomerically or diastereomerically (as relevant) enriched form,including as an isolated enantiomer or diastereomer (i.e., greater than85, 90, 95, 97 or 99% pure);

(u) A process for the preparation of therapeutic products that containan effective amount of a Degronimer of Formula I, II, V or VII asdescribed herein;

(v) Use of a compound of Formula III, Formula IV, or Formula VI in aneffective amount, in the treatment of a patient, including a human, withabnormal cellular proliferation such as a tumor or cancer, an immune orautoimmune disorder or inflammatory disorder, a cardiac disorder, aninfectious disease, or other disorder that responds to such treatment;

(w) A method for manufacturing a medicament intended for the therapeutictreat a disorder characterized in that a compound of Formula III,Formula IV, or Formula VI as described herein is used in themanufacture;

(x) A compound of Formula III, Formula IV, or Formula VI as describedherein, and pharmaceutically acceptable salts, isotopic derivatives andprodrugs thereof that are useful in the treatment of an abnormalcellular proliferation such as cancer, including any of the cancersdescribed herein;

(y) Use of a compound of Formula III, Formula IV, or Formula VI andpharmaceutically acceptable salts, isotopic derivatives and prodrugsthereof in the manufacture of a medicament for the treatment of anabnormal cellular proliferation such as cancer, including any of thecancers described herein;

(z) A method for manufacturing a medicament intended for the therapeuticuse of treating an abnormal cellular proliferation such as cancer,including any of the cancers described herein, characterized in that acompound of Formula III, Formula IV, or Formula VI as described hereinis used in the manufacture;

(aa) A compound of Formula III, Formula IV, or Formula VI as describedherein, and pharmaceutically acceptable salts, isotopic derivatives andprodrugs thereof that are useful in the treatment of a tumor, includingany of the tumors described herein;

(bb) Use of a compound of Formula III, Formula IV, or Formula VI, andpharmaceutically acceptable salts, isotopic derivatives and prodrugsthereof in the manufacture of a medicament for the treatment of a tumor,including any of the tumors described herein;

(cc) A method for manufacturing a medicament intended for thetherapeutic treatment of a tumor, including any of the tumors describedherein, characterized in that a compound of Formula III, Formula IV, orFormula VI as described herein is used in the manufacture;

(dd) A compound of Formula III, Formula IV, or Formula VI as describedherein, and pharmaceutically acceptable salts, isotopic derivatives andprodrugs thereof that are useful in the treatment of an immune,autoimmune or inflammatory disorder;

(ee) Use of a compound of Formula III, Formula IV, or Formula VI andpharmaceutically acceptable salts and prodrugs thereof in themanufacture of a medicament for the treatment of an immune, autoimmuneor inflammatory disorder;

(ff) A method for manufacturing a medicament intended for thetherapeutic treatment of an immune, autoimmune or inflammatory disorder,characterized in that a compound of Formula III, Formula IV, or FormulaVI, as described herein is used in the manufacture;

(gg) A pharmaceutical formulation comprising an effective host-treatingamount, such as a human-treating amount of the compound of Formula III,Formula IV, or Formula VI or a pharmaceutically acceptable salt orprodrug thereof together with a pharmaceutically acceptable carrier ordiluent;

(hh) A compound of Formula III, Formula IV, or Formula VI as describedherein as a mixture of enantiomers or diastereomers (as relevant),including as a racemate;

(ii) A compound of Formula III, Formula IV, or Formula VI as describedherein in enantiomerically or diastereomerically (as relevant) enrichedform, including as an isolated enantiomer or diastereomer (i.e., greaterthan 85, 90, 95, 97 or 99% pure); and

(jj) A process for the preparation of therapeutic products that containan effective amount of a compound of Formula III, Formula IV, or FormulaVI as described herein.

BRIEF DESCRIPTION OF FIGURES

FIG. 1A-1C present examples of Retenoid X Receptor (RXR) TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 1D-IF present examples of general Dihydrofolate reductase (DHFR)Targeting Ligands wherein R is the point at which the Linker isattached.

FIG. 1G presents examples of Bacillus anthracis Dihydrofolate reductase(BaDHFR) Targeting Ligands wherein R is the point at which the Linker isattached.

FIG. 1H-1J present examples of Heat Shock Protein 90 (HSP90) TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 1K-1Q present examples of General Kinase and Phosphatase TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 1R-1S present examples of Tyrosine Kinase Targeting Ligands whereinR is the point at which the Linker is attached.

FIG. 1T presents examples of Aurora Kinase Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 1U presents examples of Protein Tyrosine Phosphatase TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 1V presents examples of ALK Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1W presents examples of ABL Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1X presents examples of JAK2 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1Y-1Z present examples of MET Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1AA presents examples of mTORC1 and/or mTORC2 Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 1BB-1CC present examples of Mast/stem cell growth factor receptor(SCFR), also known as c-KIT receptor, Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1DD presents examples of IGF1R and/or IR Targeting Ligands whereinR is the point at which the Linker is attached.

FIG. 1EE-1FF present examples of HDM2 and/or MDM2 Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 1GG-1MM present examples of BET Bromodomain-Containing ProteinTargeting Ligands wherein R is the point at which the Linker isattached.

FIG. 1NN presents examples of HDAC Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1OO presents examples of RAF Receptor Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 1PP presents examples of FKBP Receptor Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 1QQ-1TT present examples of Androgen Receptor Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 1UU presents examples of Estrogen Receptor Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 1VV-1WW present examples of Thyroid Hormone Receptor TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 1XX presents examples of HIV Protease Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 1YY presents examples of HIV Integrase Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 1ZZ presents examples of HCV Protease Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 1AAA presents examples of AP1 and/or AP2 Targeting Ligands whereinR is the point at which the Linker is attached.

FIG. 1BBB-1CCC present examples of MCL-1 Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 1DDD presents examples of IDH1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 1EEE-1FFF present examples of RAS or RASK Targeting Ligands whereinR is the point at which the Linker is attached.

FIG. 1GGG presents examples of MERTK or MER Targeting Ligands wherein Ris the point at which the linker is attached.

FIG. 1HHH-1III present examples of EGFR Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 1JJJ-1KKK present examples of FLT3 Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 1LLL presents examples of SMRCA2 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 2A presents examples of the kinase inhibitor Targeting LigandsU09-CX-5279 (derivatized) wherein R is the point at which the Linker isattached.

FIG. 2B-2C present examples of kinase inhibitor Targeting Ligands,including the kinase inhibitor compounds Y1W and Y1X (derivatized)wherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the kinase inhibitors identified inMillan et al. “Design and Synthesis of Inhaled P38 Inhibitors for theTreatment of Chronic Obstructive Pulmonary Disease” J. Med. Chem., 54:7797 (2011).

FIG. 2D presents examples of kinase inhibitor Targeting Ligands,including the kinase inhibitor compounds 6TP and 0TP (derivatized)wherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the kinase inhibitors identified inSchenkel et al. “Discovery of Potent and Highly Selective ThienopyridineJanus Kinase 2 Inhibitors” J. Med. Chem., 54 (24): 8440-8450 (2011).

FIG. 2E presents examples of kinase inhibitor Targeting Ligands,including the kinase inhibitor compound 07U wherein R is the point atwhich the Linker is attached. For additional examples and relatedligands, see, the kinase inhibitors identified in Van Eis et al. “26-Naphthyridines as potent and selective inhibitors of the novel proteinkinase C isozymes” Biorg. Med. Chem. Lett., 21(24): 7367-72 (2011).

FIG. 2F presents examples of kinase inhibitor Targeting Ligands,including the kinase inhibitor compound YCF, wherein R is the point atwhich the Linker is attached. For additional examples and relatedligands, see, the kinase inhibitors identified in Lountos et al.“Structural Characterization of Inhibitor Complexes with CheckpointKinase 2 (Chk2) a Drug Target for Cancer Therapy” J. Struct. Biol., 176:292 (2011).

FIG. 2G-2H present examples of kinase inhibitor Targeting Ligands,including the kinase inhibitors XK9 and NXP (derivatized) wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the kinase inhibitors identified in Lountos et al.“Structural Characterization of Inhibitor Complexes with CheckpointKinase 2 (Chk2) a Drug Target for Cancer Therapy” J. Struct. Biol., 176:292 (2011).

FIG. 2I-2J present examples of kinase inhibitor Targeting Ligandswherein R is the point at which the Linker r is attached.

FIG. 2K-2M present examples of Cyclin Dependent Kinase 9 (CDK9)Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, Baumli etal. “The structure of P-TEFb (CDK9/cyclin Ti) its complex withflavopiridol and regulation by phosphorylation.” Embo J., 27: 1907-1918(2008); Bettayeb et al. “CDK Inhibitors Roscovitine and CR8 TriggerMcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells.”Genes Cancer, 1: 369-380 (2010); Baumli et al. “Halogen bonds form thebasis for selective P-TEFb inhibition by DRB.” Chem. Biol. 17: 931-936(2010); Hole et al. “Comparative Structural and Functional Studies of4-(Thiazol-5-Yl)-2-(Phenylamino)Pyrimidine-5-Carbonitrile Cdk9Inhibitors Suggest the Basis for Isotype Selectivity.” J. Med. Chem. 56:660 (2013); Lucking et al. “Identification of the potent and highlyselective PTEFb inhibitor BAY 1251152 for the treatment of cancer—Fromp.o. to i.v. application via scaffold hops.” Lücking et al. U. AACRAnnual Meeting, Apr. 1-5, 2017 Washington, D.C. USA.

FIG. 2N-2P present examples of Cyclin Dependent Kinase 4/6 (CDK4/6)Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, Lu H.;Schulze-Gahmen U.; “Toward understanding the structural basis ofcyclin-dependent kinase 6 specific inhibition.” J. Med. Chem., 49:3826-3831 (2006); 4-(Pyrazol-4-yl)-pyrimidines as selective inhibitorsof cyclin-dependent kinase 4/6. Cho et al. (2010) J. Med. Chem. 53:7938-7957; Cho Y. S. et al. “Fragment-Based Discovery of7-Azabenzimidazoles as Potent Highly Selective and Orally Active CDK4/6Inhibitors.” ACS Med Chem Lett 3: 445-449 (2012); Li Z. et al.“Discovery of AMG 925 a FLT3 and CDK4 dual kinase inhibitor withpreferential affinity for the activated state of FLT3.” J. Med. Chem.57: 3430-3449 (2014); Chen P. et al. “Spectrum and Degree of CDK DrugInteractions Predicts Clinical Performance.” Mol. Cancer Ther. 15:2273-2281 (2016).

FIG. 2Q presents examples of Cyclin Dependent Kinase 12 and/or CyclinDependent Kinase 13 Targeting Ligands wherein R is the point at whichthe Linker is attached. For additional examples and related ligands,see, Zhang T. et al. “Covalent Targeting of Remote Cysteine Residues toDevelop Cdk12 and Cdk13 Inhibitors.” Nat. Chem. Biol. 12: 876 (2016).

FIG. 2R-2S present examples of Glucocorticoid Receptor Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 2T-2U present examples of RasG12C Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 2V presents examples of Her3 Targeting Ligands wherein R is thepoint at which the Linker is attached and R′ is

FIG. 2W presents examples of Bcl-2 or Bcl-XL Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 2X-2NN present examples of BCL2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Toure B. B. et al. “The role of the acidity ofN-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-proteininteractions.” ACS Med Chem Lett, 4: 186-190 (2013); Porter J. e.t al.“Tetrahydroisoquinoline Amide Substituted Phenyl Pyrazoles as SelectiveBcl-2 Inhibitors” Bioorg. Med. Chem. Lett. 19: 230 (2009); Souers A. J.et al. “ABT-199 a potent and selective BCL-2 inhibitor achievesantitumor activity while sparing platelets.” Nature Med. 19: 202-208(2013); Angelo Aguilar et al. “A Potent and Highly EfficaciousBcl-2/Bcl-xL Inhibitor” J Med Chem. 56(7): 3048-3067 (2013); LongchuanBai et al. “BM-1197: A Novel and Specific Bcl-2/Bcl-xL InhibitorInducing Complete and Long-Lasting Tumor Regression In Vivo” PLoS ONE9(6): e99404; Fariba Ne´matil et al. “Targeting Bcl-2/Bcl-XL InducesAntitumor Activity in Uveal Melanoma Patient-Derived Xenografts” PLoSONE 9(1): e80836; WO2015011396 titled “Novel derivatives of indole andpyrrole method for the production thereof and pharmaceuticalcompositions containing same”; WO2008060569A1 titled “Compounds andmethods for inhibiting the interaction of Bcl proteins with bindingpartners”; “Inhibitors of the anti-apoptotic Bcl-2 proteins: a patentreview” Expert Opin. Ther. Patents 22(1):2008 (2012); and, Porter et al.“Tetrahydroisoquinoline amide substituted phenyl pyrazoles as selectiveBcl-2 inhibitors” Bioorg Med Chem Lett., 19(1):230-3 (2009).

FIG. 2OO-2UU present examples of BCL-XL Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, Zhi-Fu Tao et al. “Discovery of a Potent andSelective BCL-XL Inhibitor with in Vivo Activity” ACS Med. Chem. Lett.,5: 1088-1093 (2014); Joel D. Leverson et al. “Exploiting selective BCL-2family inhibitors to dissect cell survival dependencies and defineimproved strategies for cancer therapy” Science Translational Medicine,7:279ra40 (2015); and, the crystal structure PDB 3ZK6 (Guillaume Lesseneet al. “Structure-guided design of a selective BCL-XL inhibitor” NatureChemical Biology 9: 390-397 (2013))

FIG. 2VV presents examples of PPAR-gamma Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 2WW-2YY present examples of EGFR Targeting Ligands that target theEGFR L858R mutant, including erlotinib, gefitnib, afatinib, neratinib,and dacomitinib, wherein R is the point at which the Linker is attached.

FIG. 2ZZ-2FFF present examples of EGFR Targeting Ligands that target theEGFR T790M mutant, including osimertinib, rociletinib, olmutinib,naquotinib, nazartinib, PF-06747775, Icotinib, Neratinib Avitinib,Tarloxotinib, PF-0645998, Tesevatinib, Transtinib, WZ-3146, WZ8040, andCNX-2006, wherein R is the point at which the Linker is attached.

FIG. 2GGG presents examples of EGFR Targeting Ligands that target theEGFR C797S mutant, including EAI045, wherein R is the point at which theLinker is attached.

FIG. 2HHH presents examples of BCR-ABL Targeting Ligands that target theBCR-ABL T315I mutantm including Nilotinib and Dasatinib, wherein R isthe point at which the Linker is attached. See for example, the crystalstructure PDB 3CS9.

FIG. 2III presents examples of Targeting Ligands that target BCR-ABL,including Nilotinib, Dasatinib Ponatinib and Bosutinib, wherein R is thepoint at which the Linker is attached.

FIG. 2JJJ-2KKK present examples of ALK Targeting Ligands that target theALK L1196M mutant including Ceritinib, wherein R is the point at whichthe Linker is attached. See for example, the crystal structure PDB 4MKC.

FIG. 2LLL presents examples of JAK2 Targeting Ligands that target theJAK2V617F mutant, including Ruxolitinib, wherein R is the point at whichthe Linker is attached.

FIG. 2MMM presents examples of BRAF Targeting Ligands that target theBRAF V600E mutant including Vemurafenib, wherein R is the point at whichthe Linker is attached. For additional examples and related ligands,see, the crystal structure PBD 3OG7.

FIG. 2NNN presents examples of BRAF Targeting Ligands, includingDabrafenib, wherein R is the point at which the Linker is attached.

FIG. 2OOO presents examples of LRRK2 Targeting Ligands that target theLRRK2 R1441C mutant wherein R is the point at which the Linker isattached.

FIG. 2PPP presents examples of LRRK2 Targeting Ligands that target theLRRK2 G2019S mutant wherein R is the point at which the Linker isattached.

FIG. 2QQQ presents examples of LRRK2 Targeting Ligands that target theLRRK2 I2020T mutant wherein R is the point at which the Linker isattached.

FIG. 2RRR-2TTT present examples of PDGFRa Targeting Ligands that targetthe PDGFRα T674I mutant, including AG-1478, CHEMBL94431, Dovitinib,erlotinib, gefitinib, imatinib, Janex 1, Pazopanib, PD153035, Sorafenib,Sunitinib, and WHI-P180, wherein R is the point at which the Linker isattached.

FIG. 2UUU presents examples of RET Targeting Ligands that target the RETG691S mutant, including tozasertib, wherein R is the point at which theLinker is attached.

FIG. 2VVV presents examples of RET Targeting Ligands that target the RETR749T mutant, including tozasertib, wherein R is the point at which theLinker is attached.

FIG. 2WWW presents examples of RET Targeting Ligands that target the RETE762Q mutant, including tozasertib, wherein R is the point at which theLinker is attached.

FIG. 2XXX presents examples of RET Targeting Ligands that target the RETY791F mutant, including tozasertib, wherein R is the point at which theLinker is attached.

FIG. 2YYY presents examples of RET Targeting Ligands that target the RETV804M mutant, including tozasertib, wherein R is the point at which theLinker is attached.

FIG. 2ZZZ presents examples of RET Targeting Ligands that target the RETM918T mutant, including tozasertib, wherein R is the point at which theLinker is attached.

FIG. 2AAAA presents examples of Fatty Acid Binding Protein TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 2BBBB presents examples of 5-Lipoxygenase Activating Protein (FLAP)Targeting Ligands wherein R is the point at which the Linker isattached.

FIG. 2CCCC presents examples of Kringle Domain V 4BVV Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 2DDDD presents examples of Lactoylglutathione Lyase TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 2EEEE-2FFFF present examples of mPGES-1 Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 2GGGG-2JJJJ present examples of Factor Xa Targeting Ligands whereinR is the point at which the Linker is attached. For additional examplesand related ligands, see, Maignan S. et al. “Crystal structures of humanfactor Xa complexed with potent inhibitors.” J. Med. Chem. 43: 3226-3232(2000); Matsusue T. et al. “Factor Xa Specific Inhibitor that Inducesthe Novel Binding Model in Complex with Human Fxa.” (to be published);the crystal structures PDB liqh, liqi, liqk, and liqm; Adler M. et al.“Crystal Structures of Two Potent Nonamidine Inhibitors Bound to FactorXa.” Biochemistry 41: 15514-15523 (2002); Roehrig S. et al. “Discoveryof the Novel Antithrombotic Agent5-Chloro-N-({(5S)-2-Oxo-3-[4-(3-Oxomorpholin-4-Yl)Phenyl]-13-Oxazolidin-5-Yl})Methyl)Thiophene-2-Carboxamide (Bay 59-7939): An OralDirect Factor Xa Inhibitor.” J. Med. Chem. 48: 5900 (2005); Anselm L. etal. “Discovery of a Factor Xa Inhibitor (3R 4R)-1-(22-Difluoro-Ethyl)-Pyrrolidine-3 4-Dicarboxylic Acid3-[(5-Chloro-Pyridin-2-Yl)-Amide]4-{[2-Fluoro-4-(2-Oxo-2H-Pyridin-1-Yl)-Phenyl]-Amide} as a ClinicalCandidate.” Bioorg. Med. Chem. 20: 5313 (2010); and, Pinto D. J. et al.“Discovery of1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4 5 67-tetrahydro-1H-pyrazolo[3 4-c]pyridine-3-carboxamide (ApixabanBMS-562247) a Highly Potent Selective Efficacious and OrallyBioavailable Inhibitor of Blood Coagulation Factor Xa.” J. Med. Chem.50: 5339-5356 (2007).

FIG. 2KKKK presents examples of Kallikrein 7 Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, Maibaum J. et al. “Small-molecule factor Dinhibitors targeting the alternative complement pathway.” Nat. Chem.Biol. 12: 1105-1110 (2016).

FIG. 2LLLL-2MMMM present examples of Cathepsin K Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, Rankovic Z. et al. “Design andoptimization of a series of novel 2-cyano-pyrimidines as cathepsin Kinhibitors” Bioorg. Med. Chem. Lett. 20: 1524-1527 (2010); and, Cai J.et al. “Trifluoromethylphenyl as P2 for ketoamide-based cathepsin Sinhibitors.” Bioorg. Med. Chem. Lett. 20: 6890-6894 (2010).

FIG. 2NNNN presents examples of Cathepsin L Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, Kuhn B. et al. “Prospective Evaluation of FreeEnergy Calculations for the Prioritization of Cathepsin L Inhibitors.”J. Med. Chem. 60: 2485-2497 (2017).

FIG. 2OOOO presents examples of Cathepsin S Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, Jadhav P. K. et al. “Discovery of Cathepsin SInhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm” ACSMed. Chem. Lett. 5: 1138-1142.” (2014).

FIG. 2PPPP-2SSSS present examples of MTH1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, Kettle J. G. et al. “Potent and SelectiveInhibitors of Mth1 Probe its Role in Cancer Cell Survival.” J. Med.Chem. 59: 2346 (2016); Huber K. V. M. et al. “Stereospecific Targetingof Mth1 by (S)-Crizotinib as an Anticancer Strategy.” Nature 508: 222(2014); Gad H. et al. “MTH1 inhibition eradicates cancer by preventingsanitation of the dNTP pool.” Nature 508: 215-221 (2014); Nissink J. W.M. et al. “Mth1 Substrate Recognition—an Example of SpecificPromiscuity.” Plos One 11: 51154 (2016); and, Manuel Ellermann et al.“Novel class of potent and selective inhibitors efface MTH1 asbroad-spectrum cancer target.” AACR National Meeting Abstract 5226,2017.

FIG. 2TTTT-2ZZZZ present examples of MDM2 and/or MDM4 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, Popowicz G. M. et al. “Structures oflow molecular weight inhibitors bound to MDMX and MDM2 reveal newapproaches for p53-MDMX/MDM2 antagonist drug discovery.” Cell Cycle, 9(2010); Miyazaki M. et al. “Synthesis and evaluation of novel orallyactive p53-MDM2 interaction inhibitors.” Bioorg. Med. Chem. 21:4319-4331 (2013); Miyazaki M. et al. “Discovery of DS-5272 as apromising candidate: A potent and orally active p53-MDM2 interactioninhibitor.” Bioorg Med Chem. 23: 2360-7 (2015); Holzer P. et al.“Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A HighlyPotent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trialsin p53 wt Tumors.” J. Med. Chem. 58: 6348-6358 (2015); Gonzalez-Lopez deTuriso F. et al. “Rational Design and Binding Mode Duality of MDM2-p53Inhibitors.” J. Med. Chem. 56: 4053-4070 (2013); Gessier F. et al.“Discovery of dihydroisoquinolinone derivatives as novel inhibitors ofthe p53-MDM2 interaction with a distinct binding mode.” Bioorg. Med.Chem. Lett. 25: 3621-3625 (2015); Fry D. C. et al. “Deconstruction of anutlin: dissecting the binding determinants of a potent protein-proteininteraction inhibitor.” ACS Med Chem Lett 4: 660-665 (2013); Ding Q. etal. “Discovery of RG7388 a Potent and Selective p53-MDM2 Inhibitor inClinical Development.” J. Med. Chem. 56: 5979-5983 (2013); Wang S. etal. “SAR405838: an optimized inhibitor of MDM2-p53 interaction thatinduces complete and durable tumor regression.” Cancer Res. 74:5855-5865 (2014); Rew Y. et al. “Discovery of AM-7209 a Potent andSelective 4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction.” J.Med. Chem. 57: 10499-10511 (2014); Bogen S. L. et al. “Discovery ofNovel 3 3-Disubstituted Piperidines as Orally Bioavailable Potent andEfficacious HDM2-p53 Inhibitors.” ACS Med. Chem. Lett. 7: 324-329(2016); and, Sun D. et al. “Discovery of AMG 232 a Potent Selective andOrally Bioavailable MDM2-p53 Inhibitor in Clinical Development.” J. Med.Chem. 57: 1454-1472 (2014).

FIG. 2AAAAA-2EEEEE present examples of PARP1, PARP2, and/or PARP3Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, Iwashita A.et al. “Discovery of quinazolinone and quinoxaline derivatives as potentand selective poly(ADP-ribose) polymerase-1/2 inhibitors.” Febs Lett.579: 1389-1393 (2005); the crystal structure PDB 2RCW (PARP complexedwith A861695, Park C. H.); the crystal structure PDB 2RD6 (PARPcomplexed with A861696, Park C. H.); the crystal structure PDB 3GN7;Miyashiro J. et al. “Synthesis and SAR of novel tricyclic quinoxalinoneinhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)” Bioorg. Med. Chem.Lett. 19: 4050-4054 (2009); Gandhi V. B. et al. “Discovery and SAR ofsubstituted 3-oxoisoindoline-4-carboxamides as potent inhibitors ofpoly(ADP-ribose) polymerase (PARP) for the treatment of cancer.” Bioorg.Med. Chem. Lett. 20: 1023-1026 (2010); Penning T. D. et al.“Optimization of phenyl-substituted benzimidazole carboxamidepoly(ADP-ribose) polymerase inhibitors: identification of(S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide(A-966492) a highly potent and efficacious inhibitor.” J. Med. Chem. 53:3142-3153 (2010); Ye N. et al. “Design, Synthesis, and BiologicalEvaluation of a Series of Benzo[de][1 7]naphthyridin-7(8H)-ones Bearinga Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors.” J.Med Chem. 56: 2885-2903 (2013); Patel M. R. et al. “Discovery andStructure-Activity Relationship of Novel 23-Dihydrobenzofuran-7-carboxamide and 23-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives asPoly(ADP-ribose)polymerase-1 Inhibitors.” J. Med. Chem. 57: 5579-5601(2014); Thorsell A. G. et al. “Structural Basis for Potency andPromiscuity in Poly(ADP-ribose) Polymerase (PARP) and TankyraseInhibitors.” J. Med. Chem. 60:1262-1271 (2012); the crystal structurePDB 4RV6 (“Human ARTD1 (PARP1) catalytic domain in complex withinhibitor Rucaparib”, Karlberg T. et al.); Papeo G. M. E. et al.“Discovery of 2-[1-(44-Difluorocyclohexyl)Piperidin-4-Yl]-6-Fluoro-3-Oxo-23-Dihydro-1H-Isoindole-4-Carboxamide (Nms-P118): A Potent OrallyAvailable and Highly Selective Parp-1 Inhibitor for Cancer Therapy.” J.Med. Chem. 58: 6875 (2015); Kinoshita T. et al. “Inhibitor-inducedstructural change of the active site of human poly(ADP-ribose)polymerase.” Febs Lett. 556: 43-46 (2004); and, Gangloff A. R. et al.“Discovery of novel benzo[b][1 4]oxazin-3(4H)-ones aspoly(ADP-ribose)polymerase inhibitors.” Bioorg. Med. Chem. Lett. 23:4501-4505 (2013).

FIG. 2FFFFF-2GGGGG present examples of PARP14 Targeting Ligands whereinR is the point at which the Linker is attached.

FIG. 2HHHHH presents examples of PARP15 Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 2IIIII presents examples of PDZ domain Targeting Ligands wherein Ris the point at which the Linker(s) are attached.

FIG. 2JJJJJ presents examples of Phospholipase A2 domain TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 2KKKKK presents examples of Protein S100-A7 2WOS Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 2LLLLL-2MMMMM present examples of Saposin-B Targeting Ligandswherein R is the point at which the Linker is attached.

FIG. 2NNNNN-2OOOOO present examples of Sec7 Targeting Ligands wherein Ris the point at which the Linker is attached.

FIG. 2PPPPP-2QQQQQ present examples of SH2 domain of pp60 Src TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 2RRRRR presents examples of Tank1 Targeting Ligands wherein R isthe point at which the Linker is attached.

FIG. 2SSSSS presents examples of Ubc9 SUMO E2 ligase SF6D TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 2TTTTT presents examples of Src Targenting Ligands, includingAP23464, wherein R is the point at which the Linker is attached.

FIG. 2UUUUU-2XXXXX present examples of Src-AS1 and/or Src AS2 TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 2YYYYY presents examples of JAK3 Targeting Ligands, includingTofacitinib, wherein R is the point at which the Linker is attached.

FIG. 2ZZZZZ presents examples of ABL Targeting Ligands, includingTofacitinib and Ponatinib, wherein R is the point at which the Linker isattached.

FIG. 3A-3B present examples of MEK1 Targeting Ligands, includingPD318088, Trametinib and G-573, wherein R is the point at which theLinker is attached.

FIG. 3C presents examples of KIT Targeting Ligands, includingRegorafenib, wherein R is the point at which the Linker is attached.

FIG. 3D-3E present examples of HIV Reverse Transcriptase TargetingLigands, including Efavirenz, Tenofovir, Emtricitabine, Ritonavir,Raltegravir, and Atazanavir, wherein R is the point at which the Linkeris attached.

FIG. 3F-3G present examples of HIV Protease Targeting Ligands, includingRitonavir, Raltegravir, and Atazanavir, wherein R is the point at whichthe Linker is attached.

FIG. 3H-3I present examples of KSR1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3J-3L present examples of CNNTB1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3M presents examples of BCL6 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3N-3O present examples of PAK1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3P-3R present examples of PAK4 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3S-3T present examples of TNIK Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3U presents examples of MEN1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3V-3W present examples of ERK1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3X presents examples of IDO1 Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3Y presents examples of CBP Targeting Ligands wherein R is thepoint at which the Linker is attached.

FIG. 3Z-3SS present examples of MCL1 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Tanaka Y. et al “Discovery of potent Mcl-1/Bcl-xLdual inhibitors by using a hybridization strategy based on structuralanalysis of target proteins.” J. Med. Chem. 56: 9635-9645 (2013);Friberg A. et al. “Discovery of potent myeloid cell leukemia 1 (Mcl-1)inhibitors using fragment-based methods and structure-based design.” J.Med. Chem. 56: 15-30 (2013); Petros A. M. et al “Fragment-baseddiscovery of potent inhibitors of the anti-apoptotic MCL-1 protein.”Bioorg. Med. Chem. Lett. 24: 1484-1488 (2014); Burke J. P. et al.“Discovery of tricyclic indoles that potently inhibit mcl-1 usingfragment-based methods and structure-based design.” J. Med. Chem. 58:3794-3805 (2015); Pelz N. F. et al. “Discovery of2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) InhibitorsUsing Fragment-Based Methods.” J. Med. Chem. 59: 2054-2066 (2016);Clifton M. C. et al. “A Maltose-Binding Protein Fusion Construct Yieldsa Robust Crystallography Platform for MCL1.” Plos One 10:e0125010-e0125010 (2015); Kotschy A et al. “The MCL1 inhibitor S63845 istolerable and effective in diverse cancer models. Nature 538:477-482(2016); EP 2886545 A1 titled “New thienopyrimidine derivatives a processfor their preparation and pharmaceutical compositions containing them”;Jeffrey W. Johannes et al. “Structure Based Design of Non-NaturalPeptidic Macrocyclic Mcl-1 Inhibitors” ACS Med. Chem. Lett. (2017); DOI:10.1021/acsmedchemlett.6b00464; Bruncko M. et al. “Structure-GuidedDesign of a Series of MCL-1 Inhibitors with High Affinity andSelectivity.” J. Med. Chem. 58: 2180-2194 (2015); Taekyu Lee et al.“Discovery and biological characterization of potent myeloid cellleukemia-1 inhibitors.” FEBS Letters 591: 240-251 (2017); Chen L. et al.“Structure-Based Design of 3-Carboxy-Substituted 1 2 34-Tetrahydroquinolines as Inhibitors of Myeloid Cell Leukemia-1(Mcl-1).” Org. Biomol Chem. 14:5505-5510 (2016); US 2016/0068545 titled“Tetrahydronaphthalene derivatives that inhibit mcl-1 protein”; WO2016207217 A1 titled “Preparation of new bicyclic derivatives aspro-apoptotic agents”; Gizem Akçay et al. “Inhibition of Mcl-1 throughcovalent modification of a noncatalytic lysine side chain” NatureChemical Biology 12: 931-936 (2016).

FIG. 3TT presents examples of ASH1L Targeting Ligands wherein R is thepoint at which the Linker is attached. See for example, the crystalstructure PDB 4YNM (“Human ASH1L SET domain in complex with S-adenosylmethionine (SAM)” Rogawski D. S. et al.)

FIG. 3UU-3WW present examples of ATAD2 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, Chaikuad A. et al. “Structure-based approachestowards identification of fragments for the low-druggability ATAD2bromodomain” Med Chem Comm 5: 1843-1848 (2014); Poncet-Montange G. etal. “Observed bromodomain flexibility reveals histone peptide- and smallmolecule ligand-compatible forms of ATAD2.” Biochem. J. 466: 337-346(2015); Harner M. J. et al. “Fragment-Based Screening of the Bromodomainof ATAD2.” J. Med. Chem. 57: 9687-9692 (2014); Demont E. H. et al.“Fragment-Based Discovery of Low-Micromolar Atad2 BromodomainInhibitors.” J. Med. Chem. 58: 5649 (2015); and, Bamborough P. et al.“Structure-Based Optimization of Naphthyridones into Potent Atad2Bromodomain Inhibitors.” J. Med. Chem. 58: 6151 (2015).

FIG. 3XX-3AAA present examples of BAZ2A and BAZ2B Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structure PDB 4CUU(“Human Baz2B in Complex with Fragment-6 N09645” Bradley A. et al.); thecrystal structure PDB 5CUA (“Second Bromodomain of Bromodomain Adjacentto Zinc Finger Domain Protein 2B (BAZ2B) in complex with1-Acetyl-4-(4-hydroxyphenyl)piperazine”. Bradley A. et al.); Ferguson F.M. et al. “Targeting low-druggability bromodomains: fragment basedscreening and inhibitor design against the BAZ2B bromodomain.” J. Med.Chem. 56: 10183-10187 (2013); Marchand J. R. et al. “Derivatives of3-Amino-2-methylpyridine as BAZ2B Bromodomain Ligands: In SilicoDiscovery and in Crystallo Validation.” J. Med. Chem. 59: 9919-9927(2016); Drouin L. et al. “Structure Enabled Design of BAZ2-ICR AChemical Probe Targeting the Bromodomains of BAZ2A and BAZ2B.” J. MedChem. 58: 2553-2559 (2015); Chen P. et al. “Discovery andcharacterization of GSK2801 a selective chemical probe for thebromodomains BAZ2A and BAZ2B.” J. Med. Chem. 59:1410-1424 (2016).

FIG. 3BBB presents examples of BRD1 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB SAME (“the CrystalStructure of the Bromodomain of Human Surface Epitope Engineered Brd1Ain Complex with 3D Consortium Fragment 4-Acetyl-Piperazin-2-One Pearce”,N. M. et al.); the crystal structure PDB 5AMF (“Crystal Structure of theBromodomain of Human Surface Epitope Engineered Brd1A in Complex with 3DConsortium Fragment Ethyl 4 5 6 7-Tetrahydro-1H-Indazole-5-Carboxylate”,Pearce N. M. et al.); the crystal structure PDB 5FG6 (“the Crystalstructure of the bromodomain of human BRD1 (BRPF2) in complex with OF-1chemical probe.”, Tallant C. et al.); Filippakopoulos P. et al. “Histonerecognition and large-scale structural analysis of the human bromodomainfamily.” Cell, 149: 214-231 (2012).

FIG. 3CCC-3EEE present examples of BRD2 Bromodomain 1 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structure PDB 2ydw; thecrystal structure PDB 2yek; the crystal structure PDB 4a9h; the crystalstructure PDB 4a9f; the crystal structure PDB 4a9i; the crystalstructure PDB 4a9m; the crystal structure PDB 4akn; the crystalstructure PDB 4alg, and the crystal structure PDB 4uyf.

FIG. 3FFF-3HHH present examples of BRD2 Bromodomain 2 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structure PDB 3oni;Filippakopoulos P. et al. “Selective Inhibition of BET Bromodomains.”Nature 468: 1067-1073 (2010); the crystal structure PDB 4j1p; McLure K.G. et al. “RVX-208: an Inducer of ApoA-I in Humans is a BET BromodomainAntagonist.” Plos One 8: e83190-e83190 (2013); Baud M. G. et al.“Chemical biology. A bump-and-hole approach to engineer controlledselectivity of BET bromodomain chemical probes” Science 346: 638-641(2014); Baud M. G. et al. “New Synthetic Routes toTriazolo-benzodiazepine Analogues: Expanding the Scope of theBump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET)Bromodomain Inhibition” J. Med. Chem. 59: 1492-1500 (2016); Gosmini R.et al. “The Discovery of I-Bet726 (Gsk1324726A) a PotentTetrahydroquinoline Apoal Up-Regulator and Selective Bet BromodomainInhibitor” J. Med. Chem. 57: 8111 (2014); the crystal structure PDB 5EK9(“Crystal structure of the second bromodomain of human BRD2 in complexwith a hydroquinolinone inhibitor”, Tallant C. et al); the crystalstructure PDB 5BT5; the crystal structure PDB 5dfd; Baud M. G. et al.“New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expandingthe Scope of the Bump-and-Hole Approach for Selective Bromo andExtra-Terminal (BET) Bromodomain Inhibition” J. Med. Chem. 59: 1492-1500(2016).

FIG. 3Hm-3JJJ present examples of BRD4 Bromodomain 1 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structure PDB 5WUU andthe crystal structure PDB 5F5Z.

FIG. 3KKK-3LLL present examples of BRD4 Bromodomain 2 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, Chung C. W. et al. “Discovery andCharacterization of Small Molecule Inhibitors of the Bet FamilyBromodomains” J. Med. Chem. 54:3827 (2011) and Ran X. et al.“Structure-Based Design of gamma-Carboline Analogues as Potent andSpecific BET Bromodomain Inhibitors” J. Med. Chem. 58: 4927-4939 (2015).

FIG. 3MMM presents examples of BRDT Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 4flp and the crystalstructure PDB 4kcx.

FIG. 3NNN-3QQQ present examples of BRD9 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 4nqn; the crystalstructure PDB 4uit; the crystal structure PDB 4uiu; the crystalstructure PDB 4uiv; the crystal structure PDB 4z6h; the crystalstructure PDB 4z6i; the crystal structure PDB 5e9v; the crystalstructure PDB 5eu1; the crystal structure PDB 5flh; and, the crystalstructure PDB 5fp2.

FIG. 3RRR presents examples of SMARCA4 PB1 and/or SMARCA2 TargetingLigands wherein R is the point at which the Linker is attached, A is Nor CH, and m is 0 1 2 3 4 5 6 7 or 8.

FIG. 3SSS-3XXX present examples of additional Bromodomain TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, Hewings et al. “35-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands.” J. Med.Chem. 54 6761-6770 (2011); Dawson et al. “Inhibition of BET Recruitmentto Chromatin as an Effective Treatment for MLL-fusion Leukemia.” Nature,478, 529-533 (2011); US 2015/0256700; US 2015/0148342; WO 2015/074064;WO 2015/067770; WO 2015/022332; WO 2015/015318; and, WO 2015/011084.

FIG. 3YYY presents examples of PB1 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 3mb4; the crystalstructure PDB 4q0n; and, the crystal structure PDB 5fh6.

FIG. 3ZZZ presents examples of SMARCA4 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure 3uvd and the crystalstructure 5dkd.

FIG. 3AAAA presents examples of SMARCA2 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure 5dkc and the crystalstructure 5dkh.

FIG. 3BBBB presents examples of TRIM24 (TIF1a) and/or BRPF1 TargetingLigands wherein R is the point at which the Linker is attached and m is0 1 2 3 4 5 6 7 or 8.

FIG. 3CCCC presents examples of TRIM24 (TIF1a) Targeting Ligands whereinR is the point at which the Linker is attached. For additional examplesand related ligands, see, Palmer W. S. et al. “Structure-Guided Designof IACS-9571: a Selective High-Affinity Dual TRIM24-BRPF1 BromodomainInhibitor.” J Med. Chem. 59: 1440-1454 (2016).

FIG. 3DDDD-3FFFF present examples of BRPF1 Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the crystal structure PDB 4uye; the crystalstructure PDB 5c7n; the crystal structure PDB 5c87; the crystalstructure PDB 5c89; the crystal structure PDB 5d7x; the crystalstructure PDB 5dya; the crystal structure PDB 5epr; the crystalstructure PDB 5eq1; the crystal structure PDB 5etb; the crystalstructure PDB 5ev9; the crystal structure PDB 5eva; the crystalstructure PDB 5ewv; the crystal structure PDB 5eww; the crystalstructure PDB 5ffy; the crystal structure PDB 5fg5; and, the crystalstructure PDB 5g4r.

FIG. 3GGGG presents examples of CECR2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Moustakim M. et al. Med. Chem. Comm. 7:2246-2264(2016) and Crawford T. et al. Journal of Med. Chem. 59; 5391-5402(2016).

FIG. 3HHHH-3OOOO present examples of CREBBP Targeting Ligands wherein Ris the point at which the Linker is attached, A is N or CH, and m is 0 12 3 4 5 6 7 or 8. For additional examples and related ligands, see, thecrystal structure PDB 3p1d; the crystal structure PDB 3svh; the crystalstructure PDB 4nr4; the crystal structure PDB 4nr5; the crystalstructure PDB 4ts8; the crystal structure PDB 4nr6; the crystalstructure PDB 4nr7; the crystal structure PDB 4nyw; the crystalstructure PDB 4nyx; the crystal structure PDB 4tqn; the crystalstructure PDB 5cgp; the crystal structure PDB 5dbm; the crystalstructure PDB 5ep7; the crystal structure PDB 5i83; the crystalstructure PDB 5i86; the crystal structure PDB 5i89; the crystalstructure PDB 5i8g; the crystal structure PDB 5j0d; the crystalstructure PDB 5ktu; the crystal structure PDB 5ktw; the crystalstructure PDB 5ktx; the crystal structure PDB 5tb6.

FIG. 3PPPP presents examples of EP300 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 5BT3.

FIG. 3QQQQ presents examples of PCAF Targeting Ligands wherein R is thepoint at which the Linker is attached. See for example, M. Ghizzoni etal. Bioorg. Med. Chem. 18: 5826-5834 (2010).

FIG. 3RRRR presents examples of PHIP Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Mol Cancer Ther. 7(9): 2621-2632 (2008).

FIG. 3SSSS presents examples of TAF1 and TAF1L Targeting Ligands whereinR is the point at which the Linker is attached. For additional examplesand related ligands, see, Picaud S. et al. Sci Adv 2: e1600760-e1600760(2016).

FIG. 3TTTT presents examples of Histone Deacetylase 2 (HDAC2) TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, Lauffer B. E. J. Biol.Chem. 288: 26926-26943 (2013); Wagner F. F. Bioorg. Med. Chem. 24:4008-4015 (2016); Bressi J. C. Bioorg. Med. Chem. Lett. 20: 3142-3145(2010); and, Lauffer B. E. J. Biol. Chem. 288: 26926-26943 (2013).

FIG. 3UUUU-3VVVV present examples of Histone Deacetylase 4 (HDAC4)Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, Burli R. W.J. Med. Chem. 56: 9934 (2013); Luckhurst C. A. ACS Med. Chem. Lett. 7:34 (2016); Bottomley M. J. J. Biol. Chem. 283: 26694-26704 (2008).

FIG. 3WWWW presents examples of Histone Deaceytlase 6 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, Harding R. J. (to be published); HaiY. Nat. Chem. Biol. 12: 741-747, (2016); and, Miyake Y. Nat. Chem. Biol.12: 748 (2016).

FIG. 3XXXX-3YYYY presents examples of Histone Deacetylase 7 TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, Lobera M. Nat. Chem. Biol.9: 319 (2013) and Schuetz A. J. Biol. Chem. 283: 11355-11363 (2008).

FIG. 3ZZZZ-3DDDDD present examples of Histone Deacetylase 8 TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, Whitehead L. Biol. Med.Chem. 19: 4626-4634 (2011); Tabackman A. A. J. Struct. Biol. 195:373-378 (2016); Dowling D. P. Biochemistry 47, 13554-13563 (2008);Somoza J. R. Biochemistry 12, 1325-1334 (2004); Decroos C. Biochemistry54: 2126-2135 (2015); Vannini A. Proc. Natl Acad. Sci. 101: 15064(2004); Vannini A. EMBO Rep. 8: 879 (2007); the crystal structure PDB5BWZ; Decroos A. ACS Chem. Biol. 9: 2157-2164 (2014); Somoza J. R.Biochemistry 12: 1325-1334 (2004); Decroos C. Biochemistry 54: 6501-6513(2015); Decroos A. ACS Chem. Biol. 9: 2157-2164 (2014); and, Dowling D.P. Biochemistry 47: 13554-13563 (2008).

FIG. 3EEEEE presents examples of Histone Acetyltransferase (KAT2B)Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, Chaikuad A.J. Med. Chem. 59: 1648-1653 (2016); the crystal structure PDB 1ZS5; and,Zeng L. J. Am. Chem. Soc. 127: 2376-2377 (2005).

FIG. 3FFFFF-3GGGGG present examples of Histone Acetyltransferase (KAT2A)Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, Ringel A. E.Acta Crystallogr. D. Struct. Biol. 72: 841-848 (2016).

FIG. 3HHHHH presents examples of Histone Acetyltransferase Type BCatalytic Unit (HAT1) Targeting Ligands wherein R is the point at whichthe Linker is attached. For additional examples and related ligands,see, the crystal structure PDB 2POW.

FIG. 3IIIII presents examples of Cyclic AMP-dependent TranscriptionFactor (ATF2) Targeting Ligands wherein R is the point at which theLinker is attached.

FIG. 3JJJJJ presents examples of Histone Acetyltransferase (KAT5)Targeting Ligands wherein R is the point at which the Linker isattached.

FIG. 3KKKKK-3MMMMM present examples of Lysine-specific histonedemethylase 1A (KDM1A) Targeting Ligands wherein R is the point at whichthe Linker is attached. For additional examples and related ligands,see, Mimasu S. Biochemistry 49: 6494-6503 (2010); Sartori L. J. Med.Chem. 60:1673-1693 (2017); and, Vianello P. J. Med. Chem. 60: 1693-1715(2017).

FIG. 3NNNNN presents examples of HDAC6 Zn Finger Domain TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 3OOOOO-3PPPPP present examples of general Lysine MethyltransferaseTargeting Ligands wherein R is the point at which the Linker isattached.

FIG. 3QQQQQ-3TTTTT present examples of DOT1L Targeting Ligands wherein Ris the point at which the Linker is attached, A is N or CH, and m is 0 12 3 4 5 6 7 or 8. For additional examples and related ligands, see, thecrystal structure PDB 5MVS (“Dot1L in complex with adenosine andinhibitor CPD1” Be C. et al.); the crystal structure PDB 5MW4 (“Dot1L incomplex inhibitor CPD7” Be C. et al.); the crystal structure PDB 5DRT(“Dot1L in complex inhibitor CPD2” Be C. et al.); Be C. et al. ACS Med.Lett. 8: 338-343 (2017); the crystal structure PDB 5JUW “(Dot1L incomplex with SS148” Yu W. et al. Structural Genomics Consortium).

FIG. 3UUUUU presents examples of EHMT1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 5TUZ (“EHMT1 in complexwith inhibitor MS0124”, Babault N. et al.).

FIG. 3VVVVV presents examples of EHMT2 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 5TUY (“EHMT2 in complexwith inhibitor MS0124”, Babault N. et al.); the PDB crystal structure5TTF (“EHMT2 in complex with inhibitor MS012”, Dong A. et al.); the PDBcrystal structure 3RJW (Dong A. et al., Structural Genomics Consortium);the PDB crystal structure 3K5K; Liu F. et al. J. Med. Chem. 52:7950-7953 (2009); and, the PDB crystal structure 4NVQ (“EHMT2 in complexwith inhibitor A-366” Sweis R. F. et al.).

FIG. 3WWWWW presents examples of SETD2 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5LSY (“SETD2 in complexwith cyproheptadine”, Tisi D. et al.); Tisi D. et al. ACS Chem. Biol.11: 3093-3105 (2016); the crystal structures PDB 5LSS, 5LSX, 5LSZ, 5LT6,5LT7, and 5LT8; the PDB crystal structure 4FMU; and, Zheng W. et al. J.Am. Chem. Soc. 134: 18004-18014 (2012).

FIG. 3XXXXX-3YYYYY present examples of SETD7 Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the PDB crystal structure 5AYF (“SETD7 incomplex with cyproheptadine.” Niwa H. et al.); the PDB crystal structure4JLG (“SETD7 in complex with (R)-PFI-2”, Dong A. et al.); the PDBcrystal structure 4JDS (Dong A. et. al Structural Genomics Consortium);the PDB crystal structure 4E47 (Walker J. R. et al. Structural GenomicsConsortium; the PDB crystal structure 3VUZ (“SETD7 in complex withAAM-1.” Niwa H. et al.); the PDB crystal structure 3VVO; and, Niwa H etal. Acta Crystallogr. Sect. D 69: 595-602 (2013).

FIG. 3ZZZZZ presents examples of SETD8 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5TH7 (“SETD8 in complexwith MS453”, Yu W. et al.) and the PDB crystal structure 5T5G (Yu W et.al.; to be published).

FIG. 4A-4B present examples of SETDB1 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5KE2 (“SETDB1 in complexwith inhibitor XST06472A”, Iqbal A. et al.); the PDB crystal structure5KE3 (“SETDB1 in complex with fragment MRT0181a”, Iqbal A. et al.); thePDB crystal structure 5KH6 (“SETDB1 in complex with fragment methyl3-(methylsulfonylamino)benzoate”, Walker J. R. et al. StructuralGenomics Consortium); and, the PDB crystal structure 5KCO (“SETDB 1 incomplex with [N]-(4-chlorophenyl)methanesulfonamide”, Walker J. R. etal.)

FIG. 4C-4P present examples of SMYD2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5KJK (“SMYD2 in complexwith inhibitor AZ13450370”, Cowen S. D. et al.); the PDB crystalstructure 5KJM (“SMYD2 in complex with AZ931”, Cowen S. D. et al.); thePDB crystal structure SKJN (“SMYD2 in complex with AZ506”, Cowen S. D.et al.); the PDB crystal structure 5ARF (“SMYD2 in complex withN-[3-(4-chlorophenyl)-1-{N′-cyano-N-[3-(difluoromethoxy)phenyl]carbamimidoyl}-45-dihydro-1H-pyrazol-4-YL]-N-ethyl-2-hydroxyacetamide”, Eggert E. etal.); the PDB crystal structure 5ARG (“SMYD2 in complex with BAY598”,Eggert E. et al.); the PDB crystal structure 4YND (“SMYD2 in complexwith A-893”, Sweis R. F. et al.); the PDB crystal structure 4WUY (“SMYD2in complex with LLY-507”, Nguyen H. et al.); and, the PDB crystalstructure 3S7B (“N-cyclohexyl-N˜3˜-[2-(34-dichlorophenyl)ethyl]-N-(2-{[2-(5-hydroxy-3-oxo-3 4-dihydro-2H-14-benzoxazin-8-yl)ethyl]amino}ethyl)-beta-alaninamide”, Ferguson A. D.et al.).

FIG. 4Q-4R present examples of SMYD3 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure 5H17 (“SMYD3 in complex with5′-{[(3S)-3-amino-3-carboxypropyl][3-(dimethylamino)propyl]amino}-5′-deoxyadenosine”,Van Aller G. S. et al.); the crystal structure 5CCL (“SMYD3 in complexwith oxindole compound”, Mitchell L. H. et al.); and, the crystalstructure 5CCM (“Crystal structure of SMYD3 with SAM and EPZ030456”).

FIG. 4S presents examples of SUV4-20H1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5CPR (“SUV4-20H1 incomplex with inhibitor A-196”, Bromberg K. D. et al.).

FIG. 4T-4AA present examples of Wild Type Androgen Receptor TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, the PDB crystal structures5T8E and 5T8J (“Androgen Receptor in complex with4-(pyrrolidin-1-yl)benzonitrile derivatives”, Asano M. et al.); Asano M.et al. Bioorg. Med. Chem. Lett. 27: 1897-1901 (2017); the PDB crystalstructure 5JJM (“Androgen Receptor”, Nadal M. et al.); the PDB crystalstructure 5CJ6 (“Androgen Receptor in complex with 2-Chloro-4-[[(1R2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrilederivatives”, Saeed A. et al.); the PDB crystal structure 4QL8(“Androgen Receptor in complex with 3-alkoxy-pyrrolo[1 2-b]pyrazolinesderivatives”, Ullrich T. et al.); the PDB crystal structure 4HLW(“Androgen Receptor Binding Function 3 (BF3) Site of the Human AndrogenReceptor through Virtual Screening”, Munuganti R. S. et al.); the PDBcrystal structure 3V49 (“Androgen Receptor lbd with activator peptideand sarm inhibitor 1”, Nique F. et al.); Nique F. et al. J. Med. Chem.55: 8225-8235 (2012); the PDB crystal structure 2YHD (“Androgen Receptorin complex with AF2 small molecule inhibitor”, Axerio-Cilies P. et al.);the PDB crystal structure 3RLJ (“Androgen Receptor ligand binding domainin complex with SARM S-22”, Bohl C. E. et al.); Bohl C. E. et al. J.Med. Chem. 54: 3973-3976 (2011); the PDB crystal structure 3B5R(“Androgen Receptor ligand binding domain in complex with SARM C-31”,Bohl C. E. et al.); Bohl C. E. et al. Bioorg. Med. Chem. Lett. 18:5567-5570 (2008); the PDB crystal structure 2PIP (“Androgen Receptorligand binding domain in complex with small molecule”, Estebanez-PerpinaE. et al.); Estebanez-Perpina. E. Proc. Natl. Acad. Sci. 104:16074-16079(2007); the PDB crystal structure 2PNU (“Androgen Receptor ligandbinding domain in complex with EM5744”, Cantin L. et al.); and, the PDBcrystal structure 2HVC (“Androgen Receptor ligand binding domain incomplex with LGD2226”, Wang F. et al.). For additional related ligands,see, Matias P. M. et al. “Structural Basis for the GlucocorticoidResponse in a Mutant Human Androgen Receptor (Ar(Ccr)) Derived from anAndrogen-Independent Prostate Cancer.” J. Med. Chem. 45: 1439 (2002);Sack J. S. et al. “Crystallographic structures of the ligand-bindingdomains of the androgen receptor and its T877A mutant complexed with thenatural agonist dihydrotestosterone.” Proc. Natl. Acad. Sci. 98:4904-4909 (2001); He B. et al. “Structural basis for androgen receptorinterdomain and coactivator interactions suggests a transition innuclear receptor activation function dominance.” Mol. Cell 16: 425-438(2004); Pereira de Jesus-Tran K. “Comparison of crystal structures ofhuman androgen receptor ligand-binding domain complexed with variousagonists reveals molecular determinants responsible for bindingaffinity.” Protein Sci. 15: 987-999 (2006); Bohl C. E. et al.“Structural Basis for Accommodation of Nonsteroidal Ligands in theAndrogen Receptor.” Mol Pharmacol. 63(1):211-23 (2003); Sun C. et al.“Discovery of potent orally-active and muscle-selective androgenreceptor modulators based on an N-aryl-hydroxybicyclohydantoinscaffold.” J. Med. Chem. 49: 7596-7599 (2006); Nirschl A. A. et al.“N-aryl-oxazolidin-2-imine muscle selective androgen receptor modulatorsenhance potency through pharmacophore reorientation.” J. Med. Chem. 52:2794-2798 (2009); Bohl C. E. et al. “Effect of B-ring substitutionpattern on binding mode of propionamide selective androgen receptormodulators.” Bioorg. Med. Chem. Lett. 18: 5567-5570 (2008); Ullrich T.et al. “3-alkoxy-pyrrolo[1 2-b]pyrazolines as selective androgenreceptor modulators with ideal physicochemical properties fortransdermal administration.” J. Med. Chem. 57: 7396-7411 (2014); SaeedA. et al. “2-Chloro-4-[[(1R2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile: ATransdermal Selective Androgen Receptor Modulator (SARM) for MuscleAtrophy.” J. Med. Chem. 59: 750-755 (2016); Nique et al. “Discovery ofdiarylhydantoins as new selective androgen receptor modulators.” J. Med.Chem. 55: 8225-8235 (2012); and, Michael E. Jung et al.“Structure-Activity Relationship for Thiohydantoin Androgen ReceptorAntagonists for Castration-Resistant Prostate Cancer (CRPC).” J. Med.Chem. 53: 2779-2796 (2010).

FIG. 4BB presents examples of Mutant T877A Androgen Receptor TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, the PDB crystal structure4OGH (‘Androgen Receptor T877A-AR-LBD”, Hsu C. L. et al.) and the PDBcrystal structure 20Z7 (“Androgen Receptor T877A-AR-LBD”, Bohl C. E. etal.).

FIG. 4CC presents examples of Mutant W741L Androgen Receptor TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, the PDB crystal structure4OJB (“Androgen Receptor T877A-AR-LBD”, Hsu C. L. et al.).

FIG. 4DD-4EE presents examples of Estrogen and/or Androgen TargetingLigands wherein R is the point at which the Linker is attached.

FIG. 5A presents examples of Afatinib, a Targeting Ligands for the EGFRand ErbB2/4 receptors. R is the point at which the Linker is attached.

FIG. 5B presents examples of Axitinib, a Targeting Ligands for theVEGFR1/2/3, PDGFRβ, and Kit receptors. R is the point at which theLinker is attached.

FIG. 5C-5D present examples of Bosutinib, a Targeting Ligands for theBCR-Abl, Src, Lyn and Hck receptors. R is the point at which the Linkeris attached.

FIG. 5E presents examples of Cabozantinib, a Targeting Ligands for theRET, c-Met, VEGFR1/2/3, Kit, TrkB, Flt3, Axl, and Tie 2 receptors. R isthe point at which the Linker is attached.

FIG. 5F presents examples of Ceritinib, a Targeting Ligands for the ALK,IGF-1R, InsR, and ROS1 receptors. R is the point at which the Linker isattached.

FIG. 5G presents examples of Crizotinib, a Targeting Ligands for theALK, c-Met, HGFR, ROS1, and MST1R receptors. R is the point at which theLinker is attached.

FIG. 5H presents examples of Dabrafenib, a Targeting Ligands for theB-Raf receptor. R is the point at which the Linker is attached.

FIG. 5I presents examples of Dasatinib, a Targeting Ligands for theBCR-Abl, Src, Lck, Lyn, Yes, Fyn, Kit, EphA2, and PDGFRβ receptors. R isthe point at which the Linker is attached.

FIG. 5J presents examples of Erlotinib, a Targeting Ligands for the EGFRreceptor. R is the point at which the Linker is attached.

FIG. 5K-5M presents examples of Everolimus, a Targeting Ligands for theHER2 breast cancer receptor, the PNET receptor, the RCC receptors, theRAML receptor, and the SEGA receptor. R is the point at which the Linkeris attached.

FIG. 5N presents examples of Gefitinib, a Targeting Ligands for the EGFRand PDGFR receptors. R is the point at which the Linker is attached.

FIG. 5O presents examples of Ibrutinib, a Targeting Ligands for the BTKreceptor. R is the point at which the Linker is attached.

FIG. 5P-5Q present examples of Imatinib, a Targeting Ligands for theBCR-Abl, Kit, and PDGFR receptors. R is the point at which the Linker isattached.

FIG. 5R-5S present examples of Lapatinib, a Targeting Ligands for theEGFR and ErbB2 receptors. R is the point at which the Linker isattached.

FIG. 5T presents examples of Lenvatinib, a Targeting Ligands for theVEGFR1/2/3, FGFR1/2/3/4, PDGFRα, Kit, and RET receptors. R is the pointat which the Linker is attached.

FIG. 5U-5V a present examples of Nilotinib, a Targeting Ligands for theBCR-Abl, PDGRF, and DDR1 receptors. R is the point at which the Linkeris attached.

FIG. 5W-5X present examples of Nintedanib, a Targeting Ligands for theFGFR1/2/3, Flt3, Lck, PDGFRα/β, and VEGFR1/2/3 receptors. R is the pointat which the Linker is attached.

FIG. 5Y-5Z present examples of Palbociclib, a Targeting Ligands for theCDK4/6 receptor. R is the point at which the Linker is attached.

FIG. 5AA presents examples of Pazopanib, a Targeting Ligands for theVEGFR1/2/3, PDGFRα/β, FGFR1/3, Kit, Lck, Fms, and Itk receptors. R isthe point at which the Linker is attached.

FIG. 5BB-5CC present examples of Ponatinib, a Targeting Ligands for theBCR-Abl, T315I VEGFR, PDGFR, FGFR, EphR, Src family kinases, Kit, RET,Tie2, and Flt3 receptors. R is the point at which the Linker isattached.

FIG. 5DD presents examples of Regorafenib, a Targeting Ligands for theVEGFR1/2/3, BCR-Abl, B-Raf, B-Raf (V600E), Kit, PDGFRα/β, RET, FGFR1/2,Tie2, and Eph2A. R is the point at which the Linker is attached.

FIG. 5EE presents examples of Ruxolitinib, a Targeting Ligands for theJAK1/2 receptors. R is the point at which the Linker is attached.

FIG. 5FF-5GG present examples of Sirolimus, a Targeting Ligands for theFKBP12/mTOR receptors. R is the point at which the Linker is attached.

FIG. 5HH presents examples of Sorafenib, a Targeting Ligands for theB-Raf, CDK8, Kit, Flt3, RET, VEGFR1/2/3, and PDGFR receptors. R is thepoint at which the Linker is attached.

FIG. 5II-5JJ present examples of Sunitinib, a Targeting Ligands forPDGFRα/β, VEGFR1/2/3, Kit, Flt3, CSF-1R, RET. R is the point at whichthe Linker is attached.

FIG. 5KK-5LL present examples of Temsirolimus, a Targeting LigandsFKBP12/mTOR. R is the point at which the Linker is attached.

FIG. 5MM presents examples of Tofacitinib, a Targeting Ligands for JAK3receptors. R is the point at which the Linker is attached.

FIG. 5NN presents examples of Trametinib, a Targeting Ligands for theMEK1/2 receptors. R is the point at which the Linker is attached.

FIG. 5OO-5PP presents examples of Vandetanib, a Targeting Ligands forthe EGFR, VEGFR, RET, Tie2, Brk, and EphR. R is the point at which theLinker is attached.

FIG. 5QQ presents examples of Vemurafenib, a Targeting Ligands for theA/B/C-Raf, KSR1, and B-Raf (V600E) receptors. R is the point at whichthe Linker is attached.

FIG. 5RR presents examples of Idelasib, a Targeting Ligands for thePI3Ka receptor. R is the point at which the Linker is attached.

FIG. 5SS presents examples of Buparlisib, a Targeting Ligands for thePI3Ka receptor. R is the point at which the Linker is attached.

FIG. 5TT presents examples of Taselisib, a Targeting Ligands for thePI3Ka receptor. R is the point at which the Linker is attached.

FIG. 5UU presents examples of Copanlisib, a Targeting Ligands for thePI3Ka. R is the point at which the Linker is attached.

FIG. 5VV presents examples of Alpelisib, a Targeting Ligands for thePI3Ka. R is the point at which the Linker is attached.

FIG. 5WW presents examples of Niclosamide, a Targeting Ligands for theCNNTB1. R is the point at which the Linker is attached.

FIG. 6A-6B present examples of the BRD4 Bromodomains of PCAF and GCN5receptors 1 Targeting Ligands wherein R is the point at which the Linkeris attached. For additional examples and related ligands, see, the PDBcrystal structure 5tpx (“Discovery of a PCAF Bromodomain ChemicalProbe”); Moustakim, M., et al. Angew. Chem. Int. Ed. Engl. 56: 827(2017); the PDB crystal structure 5mlj (“Discovery of a Potent, CellPenetrant, and Selective p300/CBP-Associated Factor (PCAF)/GeneralControl Nonderepressible 5 (GCN5) Bromodomain Chemical Probe”); and,Humphreys, P. G. et al. J. Med. Chem. 60: 695 (2017).

FIG. 6C-6D present examples of G9a (EHMT2) Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the PDB crystal structure 3k5k; (“Discovery ofa 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selectiveinhibitor of histone lysine methyltransferase G9a”); Liu, F. et al. J.Med. Chem. 52: 7950 (2009); the PDB crystal structure 3rjw (“A chemicalprobe selectively inhibits G9a and GLP methyltransferase activity incells”); Vedadi, M. et al. Nat. Chem. Biol. 7: 566 (2011); the PDBcrystal structure 4nvq (“Discovery and development of potent andselective inhibitors of histone methyltransferase g9a”); and, Sweis, R.F. et al. ACSMed Chem Lett 5: 205 (2014).

FIG. 6E-6G present examples of EZH2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5ij8 (“Polycombrepressive complex 2 structure with inhibitor reveals a mechanism ofactivation and drug resistance”); Brooun, A. et al. Nat Commun 7: 11384(2016); the PDB crystal structure 51s6 (“Identification of(R)—N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide(CPI-1205), a Potent and Selective Inhibitor of HistoneMethyltransferase EZH2, Suitable for Phase I Clinical Trials for B-CellLymphomas”); Vaswani, R. G. et al. J. Med Chem. 59: 9928 (2016); and,the PDB crystal structures 5ij8 and 5ls6.

FIG. 6H-6I present examples of EED Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structures 5h15 and 5h19(“Discovery and Molecular Basis of a Diverse Set of Polycomb RepressiveComplex 2 Inhibitors Recognition by EED”); Li, L. et al. PLoS ONE 12:e0169855 (2017); and, the PDB crystal structure 5h19.

FIG. 6J presents examples of KMT5A (SETD8) Targeting Ligands wherein Ris the point at which the Linker is attached. See for example, the PDBcrystal structure 5t5g.

FIG. 6K-6L present examples of DOT1L Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 4eki (“Conformationaladaptation drives potent, selective and durable inhibition of the humanprotein methyltransferase DOT1L”); Basavapathruni, A. et al. Chem. Biol.Drug Des. 80: 971 (2012); the PDB crystal structure 4hra (“Potentinhibition of DOTIL as treatment of MLL-fusion leukemia”); Daigle, S. R.et al. Blood 122: 1017 (2013); the PDB crystal structure 5dry(“Discovery of Novel Dot1L Inhibitors through a Structure-BasedFragmentation Approach”) Chen, C. et al. ACS Med Chem. Lett. 7: 735(2016); the PDB crystal structure 5dt2 (“Discovery of Novel Dot1LInhibitors through a Structure-Based Fragmentation Approach”); and,Chen, C. et al. ACS Med Chem. Lett. 7: 735 (2016).

FIG. 6M-6N present examples of PRMT3 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 3smq (“An allostericinhibitor of protein arginine methyltransferase 3”); Siarheyeva, A. etal. Structure 20: 1425 (2012); PDB crystal structure 4ryl (“A Potent,Selective and Cell-Active Allosteric Inhibitor of Protein ArginineMethyltransferase 3 (PRMT3)”); and Kaniskan, H. U. et al. Angew. Chem.Int. Ed. Engl. 54: 5166 (2015).

FIG. 6O presents examples of CARM1 (PRMT4) Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the PDB crystal structures 2y1x and 2y1w andrelated ligands described in “Structural Basis for Carml Inhibition byIndole and Pyrazole Inhibitors.” Sack, J. S. et al. Biochem. J. 436: 331(2011).

FIG. 6P presents examples of PRMT5 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 4x61 and related ligandsdescribed in “A selective inhibitor of PRMT5 with in vivo and in vitropotency in MCL models”. Chan-Penebre, E. Nat. Chem. Biol. 11: 432(2015).

FIG. 6Q presents examples of PRMT6 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 4y30 and related ligandsdescribed in “Aryl Pyrazoles as Potent Inhibitors of ArginineMethyltransferases: Identification of the First PRMT6 Tool Compound”.Mitchell, L. H. et al. ACS Med. Chem. Lett. 6: 655 (2015).

FIG. 6R presents examples of LSD1 (KDM1A) Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 5lgu and related ligandsdescribed in “Thieno[3,2-b]pyrrole-5-carboxamides as New ReversibleInhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2:Structure-Based Drug Design and Structure-Activity Relationship”.Vianello, P. et al. J. Med. Chem. 60: 1693 (2017).

FIG. 6S-6T present examples of KDM4 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 3rvh; the PDB crystalstructure 5a7p and related ligands described in “Docking and Linking ofFragments to Discover Jumonji Histone Demethylase Inhibitors.”Korczynska, M., et al. J. Med. Chem. 59: 1580 (2016); and, the PDBcrystal structure 3f3c and related ligands described in “8-SubstitutedPyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable,KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.”Bavetsias, V. et al. J. Med. Chem. 59: 1388 (2016).

FIG. 6U presents examples of KDM5 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 3fun and related ligandsdescribed in “Structural Analysis of Human Kdm5B Guides HistoneDemethylase Inhibitor Development”. Johansson, C. et al. Nat. Chem.Biol. 12: 539 (2016) and the PDB crystal structure 5ceh and relatedligands described in “An inhibitor of KDM5 demethylases reduces survivalof drug-tolerant cancer cells”. Vinogradova, M. et al. Nat. Chem. Biol.12: 531 (2016).

FIG. 6V-6W present examples of KDM6 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 4ask and related ligandsdescribed in “A Selective Jumonji H3K27 Demethylase Inhibitor Modulatesthe Proinflammatory Macrophage Response”. Kruidenier, L. et al. Nature488: 404 (2012).

FIG. 6X presents examples of L3MBTL3 targeting ligands wherein R is thepoint at which the Linker is attached. See for example, the PDB crystalstructure 4fl6.

FIG. 6Y presents examples of Menin Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 4x5y and related ligandsdescribed in “Pharmacologic Inhibition of the Menin-MLL InteractionBlocks Progression of MLL Leukemia In Vivo” Borkin, D. et al. CancerCell 27: 589 (2015) and the PDB crystal structure 4og8 and relatedligands described in “High-Affinity Small-Molecule Inhibitors of theMenin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a NaturalProtein-Protein Interaction” He, S. et al. J. Med. Chem. 57: 1543(2014).

FIG. 6Z-6AA present examples of HDAC6 Targeting Ligands wherein R is thepoint at which the Linker is attached. See for example, the PDB crystalstructures 5kh3 and 5eei.

FIG. 6BB presents examples of HDAC7 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the PDB crystal structure 3c10 and related ligandsdescribed in “Human HDAC7 harbors a class Ha histonedeacetylase-specific zinc binding motif and cryptic deacetylaseactivity.” Schuetz, A. et al. J. Biol. Chem. 283: 11355 (2008) and thePDB crystal structure PDB 3zns and related ligands described in“Selective Class Iia Histone Deacetylase Inhibition Via a Non-ChelatingZinc Binding Group”. Lobera, M. et al. Nat. Chem. Biol. 9: 319 (2013).

FIG. 7A-7C present examples of Protein Tyrosine Phosphatase,Non-Receptor Type 1, PTP1B Targeting Ligands wherein R is the point atwhich the Linker is attached. For additional examples and relatedligands, see, the PDB crystal structure 1bzj described in “Structuralbasis for inhibition of the protein tyrosine phosphatase 1B byphosphotyrosine peptide mimetics” Groves, M. R. et al. Biochemistry 37:17773-17783 (1998); the PDB crystal structure 3cwe described in“Discovery of [(3-bromo-7-cyano-2-naphthylXdifluoro)methyl]phosphonicacid, a potent and orally active small molecule PTP1B inhibitor”. Han Y,Bioorg Med Chem Lett. 18:3200-5 (2008); the PDB crystal structures 2azrand 2b07 described in “Bicyclic and tricyclic thiophenes as proteintyrosine phosphatase 1B inhibitors.” Moretto, A. F. et al. Bioorg. Med.Chem. 14: 2162-2177 (2006); the PDB crystal structures PDB 2bgd, 2bge,2cm7, 2cm8, 2cma, 2cmb, 2cmc described in “Structure-Based Design ofProtein Tyrosine Phosphatase-1B Inhibitors”. Black, E. et al. Bioorg.Med. Chem. Lett. 15: 2503 (2005) and “Structural Basis for Inhibition ofProtein-Tyrosine Phosphatase 1B by Isothiazolidinone HeterocyclicPhosphonate Mimetics.” Ala, P. J. et al. J. Biol. Chem. 281: 32784(2006); the PDB crystal structures 2f6t and 2f6w described in“1,2,3,4-Tetrahydroisoquinolinyl sulfamic acids as phosphatase PTP1Binhibitors”. Klopfenstein, S. R. et al. Bioorg. Med. Chem. Lett. 16:1574-1578 (2006); the PDB crystal structures 2h4g, 2h4k, 2hb1 describedin “Monocyclic thiophenes as protein tyrosine phosphatase 1B inhibitors:Capturing interactions with Asp48.” Wan, Z. K. et al. Bioorg. Med. Chem.Lett. 16: 4941-4945 (2006); the PDB crystal structures 2zn7 described in“Structure-based optimization of protein tyrosine phosphatase-1 Binhibitors: capturing interactions with arginine 24”. Wan, Z. K. et al.Chem Med Chem. 3:1525-9 (2008); the PDB crystal structure 2nt7, 2ntadescribed in “Probing acid replacements of thiophene PTP1B inhibitors.”Wan, Z. K. et al. Bioorg. Med. Chem. Lett. 17: 2913-2920 (2007); and, WO2008148744 A1 assigned to Novartis AG titled “Thiadiazole derivatives asantidiabetic agents”. See also, the PDB crystal structures 1c84, 1c84,1c85, 1c86, 1c88, 118g and described in “2-(oxalylamino)-benzoic acid isa general, competitive inhibitor of protein-tyrosine phosphatases”.Andersen, H. S. et al. J. Biol. Chem. 275: 7101-7108 (2000);“Structure-based design of a low molecular weight, nonphosphorus,nonpeptide, and highly selective inhibitor of protein-tyrosinephosphatase 1B.” Iversen, L. F. et al. J. Biol. Chem. 275: 10300-10307(2000); and, “Steric hindrance as a basis for structure-based design ofselective inhibitors of protein-tyrosine phosphatases”. Iversen, L. F.et al. Biochemistry 40: 14812-14820 (2001).

FIG. 7D presents examples of Tyrosine-protein phosphatase non-receptortype 11, SHP2 Targeting Ligands wherein R is the point at which theLinker is attached. For additional examples and related ligands, see,the crystal structures PDB 4pvg and 305x and described in “Salicylicacid based small molecule inhibitor for the oncogenic Src homology-2domain containing protein tyrosine phosphatase-2 (SHP2).” Zhang, X. etal. J. Med. Chem. 53: 2482-2493 (2010); and, the crystal structure PDB5ehr and related ligands described in “Allosteric Inhibition of SHP2:Identification of a Potent, Selective, and Orally EfficaciousPhosphatase Inhibitor.” Garcia Fortanet, J. et al. J. Med. Chem. 59:7773-7782 (2016). Also, see the crystal structure PDB 5ehr described in“Allosteric Inhibition of SHP2: Identification of a Potent, Selective,and Orally Efficacious Phosphatase Inhibitor.” Garcia Fortanet, J. etal. J. Med. Chem. 59: 7773-7782 (2016) and “Allosteric inhibition ofSHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.”Chen, Y. P. et al. Nature 535: 148-152 (2016).

FIG. 7E presents examples of Tyrosine-protein phosphatase non-receptortype 22 Targeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, the crystalstructure PDB 4j51 described in “A Potent and Selective Small-MoleculeInhibitor for the Lymphoid-Specific Tyrosine Phosphatase (LYP), a TargetAssociated with Autoimmune Diseases.” He, Y. et al. J. Med. Chem. 56:4990-5008 (2013).

FIG. 7F presents examples of Scavenger mRNA-decapping enzyme DcpSTargeting Ligands wherein R is the point at which the Linker isattached. For additional examples and related ligands, see, the crystalstructures PDB 3b17, 3b19, 3bla, 4qde, 4qdv, 4qeb and related ligandsdescribed in “DcpS as a therapeutic target for spinal muscular atrophy.”Singh, J. et al. ACS Chem. Biol. 3: 711-722 (2008).

FIG. 8A-8S present examples of BRD4 Bromodomain 1 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structures PDB 3u5k and3u51 and related ligands in Filippakopoulos, P. et al. “Benzodiazepinesand benzotriazepines as protein interaction inhibitors targetingbromodomains of the BET family”, Bioorg. Med. Chem. 20: 1878-1886(2012); the crystal structure PDB 3u51; the crystal structure PDB 3zyuand related ligands described in Dawson, M. A. et al. “Inhibition of BetRecruitment to Chromatin as an Effective Treatment for Mll-FusionLeukaemia.” Nature 478: 529 (2011); the crystal structure PDB 4bwl andrelated ligands described in Mirguet, O. et al. “Naphthyridines as NovelBet Family Bromodomain Inhibitors.” Chemmedchem 9: 589 (2014); thecrystal structure PDB 4cfl and related ligands described in Dittmann, A.et al. “The Commonly Used Pi3-Kinase Probe Ly294002 is an Inhibitor ofBet Bromodomains” ACS Chem. Biol. 9: 495 (2014); the crystal structurePDB 4e96 and related ligands described in Fish, P. V. et al.“Identification of a chemical probe for bromo and extra C-terminalbromodomain inhibition through optimization of a fragment-derived hit.”J. Med. Chem. 55: 9831-9837 (2012); the crystal structure PDB 4clb andrelated ligands described in Atkinson, S. J. et al. “The Structure BasedDesign of Dual Hdac/Bet Inhibitors as Novel Epigenetic Probes.”Medchemcomm 5: 342 (2014); the crystal structure PDB 4f3i and relatedligands described in Zhang, G. et al. “Down-regulation of NF-{kappa}BTranscriptional Activity in HIV-associated Kidney Disease by BRD4Inhibition.” J. Biol. Chem. 287: 28840-28851 (2012); the crystalstructure PDB 4hx1 and related ligands described in Zhao, L.“Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of theHistone Reader BRD4 Bromodomain.” J. Med. Chem. 56: 3833-3851 (2013);the crystal structure PDB 4hxs and related ligands described in Zhao, L.et al. “Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitorsof the Histone Reader BRD4 Bromodomain.” J. Med. Chem. 56: 3833-3851(2013); the crystal structure PDB 4lrg and related ligands described inGehling, V. S. et al. “Discovery, Design, and Optimization of IsoxazoleAzepine BET Inhibitors.” ACS Med Chem Lett 4: 835-840 (2013); thecrystal structure PDB 4mep and related ligands described in Vidler, L.R. “Discovery of Novel Small-Molecule Inhibitors of BRD4 UsingStructure-Based Virtual Screening.” et al. J. Med. Chem. 56: 8073-8088(2013); the crystal structures PDB 4nr8 and PDB 4c77 and related ligandsdescribed in Ember, S. W. et al. “Acetyl-lysine Binding Site ofBromodomain-Containing Protein 4 (BRD4) Interacts with Diverse KinaseInhibitors”. ACS Chem. Biol. 9: 1160-1171 (2014); the crystal structurePDB 4o7a and related ligands described in Ember, S. W. et al.“Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4)Interacts with Diverse Kinase Inhibitors.” ACS Chem. Biol. 9: 1160-1171(2014); the crystal structure PDB 407b and related ligands described in“Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4)Interacts with Diverse Kinase Inhibitors.” Ember, S. W. et al. (2014)ACS Chem. Biol. 9: 1160-1171; the crystal structure PDB 4o7c and relatedligands described in Ember, S. W. et al. “Acetyl-lysine Binding Site ofBromodomain-Containing Protein 4 (BRD4) Interacts with Diverse KinaseInhibitors”. ACS Chem. Biol. 9: 1160-1171 (2014); the crystal structurePDB 4gpj; the crystal structure PDB 4uix and related ligands describedin Theodoulou, N. H. et al. “The Discovery of I-Brd9, a Selective CellActive Chemical Probe for Bromodomain Containing Protein 9 Inhibition”.J. Med. Chem. 59: 1425 (2016); the crystal structure PDB 4uiz andrelated ligands described in Theodoulou, N. H., et al. “The Discovery ofI-Brd9, a Selective Cell Active Chemical Probe for BromodomainContaining Protein 9 Inhibition”. J. Med. Chem. 59: 1425 (2016); thecrystal structure PDB 4wiv and related ligands described in McKeown, M.R. et al. “Biased multicomponent reactions to develop novel bromodomaininhibitors.” J. Med. Chem. 57: 9019-9027 (2014); the crystal structurePDB 4x2i and related ligands described in Taylor, A. M. et al.“Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally ActiveInhibitors of BET Bromodomains.” ACS Med. Chem. Lett. 7: 145-150 (2016);the crystal structure PDB 4yh3; And related ligands described in Duffy,B. C. “Discovery of a new chemical series of BRD4(1) inhibitors usingprotein-ligand docking and structure-guided design.” Bioorg. Med. Chem.Lett. 25: 2818-2823 (2015); the crystal structure PDB 4yh4 and relatedligands described in Duffy, B. C. “Discovery of a new chemical series ofBRD4(1) inhibitors using protein-ligand docking and structure-guideddesign.” Bioorg. Med. Chem. Lett. 25: 2818-2823 (2015); the crystalstructure PDB 4z1q and related ligands described in Taylor, A. M.“Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally ActiveInhibitors of BET Bromodomains.” ACS Med. Chem. Lett. 7: 145-150 (2016);the crystal structure PDB 4zwl; the crystal structure PDB 5a5s andrelated ligands described in Demont, E. H. “Fragment-Based Discovery ofLow-Micromolar Atad2 Bromodomain Inhibitors. J. Med. Chem. 58: 5649(2015); the crystal structure PDB 5a85 and related ligands described inBamborough, P. “Structure-Based Optimization of Naphthyridones IntoPotent Atad2 Bromodomain Inhibitors” J. Med. Chem. 58: 6151 (2015); thecrystal structure PDB 5acy and related ligands described in Sullivan, J.M. “Autism-Like Syndrome is Induced by Pharmacological Suppression ofBet Proteins in Young Mice.” J. Exp. Med. 212: 1771 (2015); the crystalstructure PDB 5ad2 and related ligands described in Waring, M. J. et al.“Potent and Selective Bivalent Inhibitors of Bet Bromodomains”. Nat.Chem. Biol. 12: 1097 (2016); the crystal structure PDB 5cfw and relatedligands described in Chekler, E. L. et al. “Transcriptional Profiling ofa Selective CREB Binding Protein Bromodomain Inhibitor HighlightsTherapeutic Opportunities.” Chem. Biol. 22: 1588-1596 (2015); thecrystal structure PDB 5cqt and related ligands described in Xue, X. etal. “Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BETBromodomain Inhibitors: Structure-Based Virtual Screening, Optimization,and Biological Evaluation”. J. Med. Chem. 59: 1565-1579 (2016); thecrystal structure PDB 5d3r and related ligands described in Hugle, M. etal. “4-Acyl Pyrrole Derivatives Yield Novel Vectors for DesigningInhibitors of the Acetyl-Lysine Recognition Site of BRD4(1)”. J. Med.Chem. 59: 1518-1530 (2016); the crystal structure PDB 5dlx and relatedligands described in Milhas, S. et al. “Protein-Protein InteractionInhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.”(2016) ACS Chem. Biol. 11: 2140-2148; the crystal structure PDB 5dlz andrelated ligands described in Milhas, S. et al. “Protein-ProteinInteraction Inhibition (2P2I)-Oriented Chemical Library Accelerates HitDiscovery.” ACS Chem. Biol. 11: 2140-2148 (2016); the crystal structurePDB 5dw2 and related ligands described in Kharenko, O. A. et al.“RVX-297—a novel BD2 selective inhibitor of BET bromodomains.” Biochem.Biophys. Res. Commun. 477: 62-67 (2016); the crystal structure PDB 5dlx;the crystal structure PDB 5his and related ligands described inAlbrecht, B. K. et al. “Identification of a BenzoisoxazoloazepineInhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Familyas a Candidate for Human Clinical Trials.” J. Med. Chem. 59: 1330-1339(2016); the crystal structure PDB 5ku3 and related ligands described inCrawford, T. D. et al. “Discovery of a Potent and Selective in VivoProbe (GNE-272) for the Bromodomains of CBP/EP300”. J. Med. Chem. 59:10549-10563 (2016); the crystal structure PDB 5lj2 and related ligandsdescribed in Bamborough, P. et al. “A Chemical Probe for the ATAD2Bromodomain.” Angew. Chem. Int. Ed. Engl. 55: 11382-11386 (2016); thecrystal structure PDB 5dlx and related ligands described in Wang, L.“Fragment-based, structure-enabled discovery of novel pyridones andpyridone macrocycles as potent bromodomain and extra-terminal domain(BET) family bromodomain inhibitors”. J. Med. Chem.10.1021/acs.jmedchem.7b00017 (2017); WO 2015169962 A1 titled“Benzimidazole derivatives as BRD4 inhibitors and their preparation anduse for the treatment of cancer” assigned to Boehringer IngelheimInternational GmbH, Germany; and, WO 2011143669 A2 titled“Azolodiazepine derivatives and their preparation, compositions andmethods for treating neoplasia, inflammatory disease and otherdisorders” assigned to Dana-Farber Cancer Institute, Inc, USA.

FIG. 8T-8V present examples of ALK Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 2xb7 and 2xba andrelated ligands described in Bossi, R. T. et al. “Crystal Structures ofAnaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors”Biochemistry 49: 6813-6825 (2010); the crystal structures PDB 2yfx,4ccb, 4ccu, amd 4cd0 snd related ligands described in Huang, Q. et al.“Design of Potent and Selective Inhibitors to Overcome ClinicalAnaplastic Lymphoma Kinase Mutations Resistant to Crizotinib.” J. Med.Chem. 57: 1170 (2014); the crystal structures PDB, 4cli, 4cmo, and 4cnhand related ligands described in Johnson, T. W. et al. “Discovery of(10R)-7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16,17-Tetrahydro-2H-8,4-(Metheno)Pyrazolo[4,3-H][2,5,11]Benzoxadiazacyclotetradecine-3-Carbonitrile(Pf-06463922), a Macrocyclic Inhibitor of Alk/Ros1 with Pre-ClinicalBrain Exposure and Broad Spectrum Potency Against Alk-ResistantMutations.” J. Med. Chem. 57: 4720 (2014); the crystal structure PDB4fny and related ligands described in Epstein, L. F. et al. “The R1275QNeuroblastoma Mutant and Certain ATP-competitive Inhibitors StabilizeAlternative Activation Loop Conformations of Anaplastic LymphomaKinase.” J. Biol. Chem. 287: 37447-37457 (2012). the crystal structurePDB 4dce and related ligands described in Bryan, M. C. et al “Rapiddevelopment of piperidine carboxamides as potent and selectiveanaplastic lymphoma kinase inhibitors.” J. Med. Chem. 55: 1698-1705(2012); the crystal structure PDB 4joa and related ligands described inGummadi, V. R. et al. “Discovery of 7-azaindole based anaplasticlymphoma kinase (ALK) inhibitors: wild type and mutant (L1196M) activecompounds with unique binding mode.” (2013) Bioorg. Med. Chem. Lett. 23:4911-4918; and, the crystal structure PDB 5iui and related ligandsdescribed in Tu, C. H. et al. “Pyrazolylamine Derivatives Reveal theConformational Switching between Type I and Type II Binding Modes ofAnaplastic Lymphoma Kinase (ALK).” J. Med Chem. 59: 3906-3919 (2016).

FIG. 8W-8X present examples of BTK Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 3gen, 3piz and relatedligands described in Marcotte, D. J. et al. “Structures of humanBruton's tyrosine kinase in active and inactive conformations suggest amechanism of activation for TEC family kinases.” Protein Sci. 19:429-439 (2010) and Kuglstatter, A. et al. “Insights into theconformational flexibility of Bruton's tyrosine kinase from multipleligand complex structures” Protein Sci. 20: 428-436” (2011); the crystalstructure PDB 3ocs, 4ot6 and related ligands described in Lou, Y. et al.“Structure-Based Drug Design of RN486, a Potent and Selective Bruton'sTyrosine Kinase (BTK) Inhibitor, for the Treatment of RheumatoidArthritis” J. Med. Chem. 58: 512-516 (2015); the crystal structures PDB5fbn and 5fbo and related ligands described in Liu, J. et al. “Discoveryof 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for theTreatment of Rheumatoid Arthritis.” ACS Med. Chem. Lett. 7: 198-203(2016); the crystal structure PDB 3pix and related ligands described inKuglstatter, A. et al. “Insights into the conformational flexibility ofBruton's tyrosine kinase from multiple ligand complex structures.”Protein Sci. 20: 428-436 (2011); and, the crystal structure PDB 3pij andrelated ligands described in Bujacz, A. et al. “Crystal structures ofthe apo form of beta-fructofuranosidase from Bifidobacterium longum andits complex with fructose.” Febs J. 278: 1728-1744 (2011).

FIG. 8Y presents examples of FLT3 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 4xuf and 4rt7 andrelated ligands described in Zorn, J. A. et al. “Crystal Structure ofthe FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220)”. PlosOne 10: e0121177-e0121177 (2015).

FIG. 8Z-8AA present examples of TNIK Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 2x7f; the crystalstructures PDB 5ax9 and 5d7a; and, related ligands described in Masuda,M. et al. “TNIK inhibition abrogates colorectal cancer stemness.” NatCommun 7: 12586-12586 (2016).

FIG. 8BB-8CC present examples of NTRK1, NTRK2, and NTRK3 TargetingLigands wherein R is the point at which the Linker is attached. Foradditional examples and related ligands, see, the crystal structure PDB4aoj and related ligands described in Wang, T. et al. “Discovery ofDisubstituted Imidazo[4,5-B]Pyridines and Purines as Potent TrkaInhibitors.” ACS Med. Chem. Lett. 3: 705 (2012); the crystal structuresPDB 4pmm, 4pmp, 4pms and 4pmt and related ligands described in Stachel,S. J. et al. “Maximizing diversity from a kinase screen: identificationof novel and selective pan-Trk inhibitors for chronic pain.” J. Med.Chem. 57: 5800-5816 (2014); the crystal structures PDB 4yps and 4yne sndrelated ligands described in Choi, H. S. et al. “(R)-2-PhenylpyrrolidineSubstituted Imidazopyridazines: A New Class of Potent and SelectivePan-TRK Inhibitors.” ACS Med. Chem. Lett. 6: 562-567 (2015); the crystalstructures PDB 4at5 and 4at3 and related ligands described in Bertrand,T. et al. “The Crystal Structures of Trka and Trkb Suggest Key Regionsfor Achieving Selective Inhibition.” J. Mol. Biol. 423: 439 (2012); and,the crystal structures PDB 3v5q and 4ymj and related ligands describedin Albaugh, P. et al. “Discovery of GNF-5837, a selective TRK Inhibitorwith efficacy in rodent cancer tumor models.” ACS Med. Chem. Lett. 3:140-145 (2012) and Choi, H. S. et al. “(R)-2-PhenylpyrrolidineSubstitute Imidazopyridazines: a New Class of Potent and SelectivePan-TRK Inhibitors.” ACS Med Chem Lett 6: 562-567 (2015).

FIG. 8DD-8EE present examples of FGFR1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 3tto and 2fgi andrelated ligands described in Brison, Y. et al. “Functional andstructural characterization of alpha-(1-2) branching sucrase derivedfrom DSR-E glucansucrase.” J. Biol. Chem. 287: 7915-7924 (2012) andMohammadi, M. et al. “Crystal structure of an angiogenesis inhibitorbound to the FGF receptor tyrosine kinase domain.” EMBO J. 17: 5896-5904(1998); the crystal structure PDB 4fb3; the crystal structure PDB 4rwkand related ligands described in Harrison, C. et al. “Polyomavirus largeT antigen binds symmetrical repeats at the viral origin in anasymmetrical manner.” J. Virol. 87: 13751-13759 (2013); the crystalstructure PDB 4rwl and related ligands described in Sohl, C. D. et al.“Illuminating the Molecular Mechanisms of Tyrosine Kinase InhibitorResistance for the FGFR1 Gatekeeper Mutation: The Achilles' Heel ofTargeted Therapy.” ACS Chem. Biol. 10: 1319-1329 (2015); the crystalstructure PDB 4uwc; the crystal structure PDB 4v01 and related ligandsdescribed in Tucker, J. A. et al. “Structural Insights Into Fgfr KinaseIsoform Selectivity: Diverse Binding Modes of Azd4547 and Ponatinib inComplex with Fgfr1 and Fgfr4.” Structure 22: 1764 (2014); the crystalstructure PDB 5a46 and related ligands described in Klein, T. et al.“Structural and Dynamic Insights Into the Energetics of Activation LoopRearrangement in Fgfr1 Kinase.” Nat. Commun. 6: 7877 (2015); and, thecrystal structure PDB Sew8 and related ligands described in Patani, H.et al. “Landscape of activating cancer mutations in FGFR kinases andtheir differential responses to inhibitors in clinical use.” Oncotarget7: 24252-24268 (2016).

FIG. 8FF presents examples of FGFR2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 2pvf and related ligandsdescribed in Chen, H. et al. “A molecular brake in the kinase hingeregion regulates the activity of receptor tyrosine kinases.” Mol. Cell27: 717-730 (2007).

FIG. 8GG presents examples of FGFR4 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 4tyi and related ligandsdescribed in Lesca, E. et al. “Structural analysis of the humanfibroblast growth factor receptor 4 kinase.” J. Mol. Biol. 426:3744-3756 (2014).

FIG. 8HH-8II present examples of MET Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 3qti and 3zcl; thecrystal structures PDB 4xmo, 4xyf, and 3zcl and related ligandsdescribed in Peterson, E. A. et al. “Discovery of Potent and Selective8-Fluorotriazolopyridine c-Met Inhibitors.” J. Med. Chem. 58: 2417-2430(2015) and Cui, J. J. et al. “Lessons from(S)-6-(1-(6-(1-Methyl-1H-Pyrazol-4-Yl)-[1,2,4]Triazolo[4,3-B]Pyridazin-3-Yl)Ethyl)Quinoline(Pf-04254644), an Inhibitor of Receptor Tyrosine Kinase C-met with HighProtein Kinase Selectivity But Broad Phosphodiesterase Family InhibitionLeading to Myocardial Degeneration in Rats.” J. Med. Chem. 56: 6651(2013); the crystal structure PDB Seyd and related ligands described inBoezio, A. A. et al. “Discovery of(R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one(AMG 337), a Potent and Selective Inhibitor of MET with High UnboundTarget Coverage and Robust In Vivo Antitumor Activity.” J. Med. Chem.59: 2328-2342 (2016); the crystal structure PDB 3ce3 and related ligandsdescribed in Kim, K. S. et al. “Discovery of pyrrolopyridine-pyridonebased inhibitors of Met kinase: synthesis, X-ray crystallographicanalysis, and biological activities.” J. Med. Chem. 51: 5330-5341(2008); the crystal structure PDB 2rfn and related ligands described inBellon, S. F. et al. “c-Met inhibitors with novel binding mode showactivity against several hereditary papillary renal cellcarcinoma-related mutations.” J. Biol. Chem. 283: 2675-2683 (2008); and,the crystal structure PDB 5dg5 and related ligands described in Smith,B. D. et al “Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis,and Microenvironment-Mediated Drug Resistance via Balanced Inhibition ofMET, TIE2, and VEGFR2.”. Mol. Cancer Ther. 14: 2023-2034 (2015).

FIG. 8JJ presents examples of JAK1 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 4ivd and related ligandsdescribed in Zak, M. et al. “Identification of C-2 HydroxyethylImidazopyrrolopyridines as Potent JAK1 Inhibitors with FavorablePhysicochemical Properties and High Selectivity over JAK2.” J. Med.Chem. 56: 4764-4785 (2013); the crystal structure PDB 5ele and relatedligands described in Vasbinder, M. M. et al. “Identification ofazabenzimidazoles as potent JAK1 selective inhibitors.” Bioorg. Med.Chem. Lett. 26: 60-67 (2016); the crystal structure PDB 5hx8 and relatedligands described in Simov, V., et al. “Structure-based design anddevelopment of (benz)imidazole pyridones as JAK1-selective kinaseinhibitors.” Bioorg. Med. Chem. Lett. 26: 1803-1808 (2016); the crystalstructure PDB 5hx8 and related ligands described in Caspers, N. L. etal. “Development of a high-throughput crystal structure-determinationplatform for JAK1 using a novel metal-chelator soaking system”. ActaCrystallogr. Sect. F 72: 840-845 (2016); and, Kettle, J. G. “Discoveryof the JAK1 selective kinase inhibitor AZD4205”, AACR National Meeting,April 2017.

FIG. 8KK-8LL present examples of JAK2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 3ugc and related ligandsdescribed in Andraos, R. et al. “Modulation of activation-loopphosphorylation by JAK inhibitors is binding mode dependent.” CancerDiscov 2: 512-523 (2012); the crystal structures PDB 5cf4, 5cf5, 5cf6and 5cf8 and related ligands described in Hart, A. C. et al.“Structure-Based Design of Selective Janus Kinase 2Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors.” ACS Med. Chem. Lett.6: 845-849 (2015); the crystal structure PDB 5aep and related ligandsdescribed in Brasca, M. G. et al “Novel Pyrrole Carboxamide Inhibitorsof Jak2 as Potential Treatment of Myeloproliferative Disorders” Bioorg.Med. Chem. 23: 2387 (2015); the crystal structures PDB 4ytf, 4yth and4yti and related ligands described in Farmer, L. J. et al. “Discovery ofVX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitorfor the Treatment of Autoimmune Diseases.” J. Med. Chem. 58: 7195-7216(2015); the crystal structure PDB 4ytf, 4yth, 4yti and related ligandsdescribed in Menet, C. J. et al. “Triazolopyridines as Selective JAK1Inhibitors: From Hit Identification to GLPG0634.” J. Med. Chem. 57:9323-9342 (2014); the crystal structure PDB 4ji9 and related ligandsdescribed in Siu, M. et al. “2-Amino-[1,2,4]triazolo[1,5-a]pyridines asJAK2 inhibitors.” Bioorg. Med. Chem. Lett. 23: 5014-5021 (2013); and,the crystal structures PDB 3io7 and 3iok and related ligands describedin Schenkel, L. B. et al. “Discovery of potent and highly selectivethienopyridine janus kinase 2 inhibitors.” J. Med. Chem. 54: 8440-8450(2011).

FIG. 8MM presents examples of JAK3 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 3zc6 and related ligandsdescribed in Lynch, S. M. et al. “Strategic Use of Conformational Biasand Structure Based Design to Identify Potent Jak3 Inhibitors withImproved Selectivity Against the Jak Family and the Kinome.” Bioorg.Med. Chem. Lett. 23: 2793 (2013); and, the crystal structures PDB 4hvd,4i6q, and 3zep and related ligands described in Soth, M. et al. “3-AmidoPyrrolopyrazine JAK Kinase Inhibitors: Development of a JAK3 vs JAK1Selective Inhibitor and Evaluation in Cellular and in Vivo Models.” J.Med. Chem. 56: 345-356 (2013) and Jaime-Figueroa, S. et al. “Discoveryof a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, aspotent JAK3 kinase inhibitors.” Bioorg. Med. Chem. Lett. 23: 2522-2526(2013).

FIG. 8NN-8OO present examples of KIT Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 1t46 and related ligandsdescribed in Mol, C. D. et al. “Structural basis for the autoinhibitionand STI-571 inhibition of c-Kit tyrosine kinase.” J. Biol. Chem. 279:31655-31663 (2004); and, the crystal structure PDB 4u0i and relatedligands described in Garner, A. P. et al. “Ponatinib Inhibits PolyclonalDrug-Resistant KIT Oncoproteins and Shows Therapeutic Potential inHeavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients.”Clin. Cancer Res. 20: 5745-5755 (2014).

FIG. 88PP-8VV present examples of EGFR Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 5hcy, 4rj4, and 5cav;Heald, R., “Noncovalent Mutant Selective Epidermal Growth FactorReceptor Inhibitors: A Lead Optimization Case Study”, J. Med. Chem. 58,8877-8895 (2015); Hanano, E. J., “Discovery of Selective and NoncovalentDiaminopyrimidine-Based Inhibitors of Epidermal Growth Factor ReceptorContaining the T790M Resistance Mutation.” J. Med. Chem., 57,10176-10191 (2014); Chan, B. K. et al. “Discovery of a Noncovalent,Mutant-Selective Epidermal Growth Factor Receptor Inhibitor” J Med.Chem. 59, 9080 (2016); the crystal structure PDB 5d41 and relatedligands described in Jia, Y. et al., “Overcoming EGFR(T790M) andEGFR(C797S) resistance with mutant-selective allosteric inhibitors”Nature 534, 129 (2016); Ward, R. A. “Structure- and reactivity-baseddevelopment of covalent inhibitors of the activating and gatekeepermutant forms of the epidermal growth factor receptor (EGFR)” J. Med.Chem. 56, 7025-7048 (2013); the crystal structure PDB 4zau and relatedligands described in “Discovery of a Potent and Selective EGFR Inhibitor(AZD9291) of Both Sensitizing and T790M Resistance Mutations That Sparesthe Wild Type Form of the Receptor” J. Med. Chem., 57 (20), 8249-8267(2014); the crystal structure PDB 5em7 and related ligands described inBryan, M. C. et al. “Pyridones as Highly Selective, NoncovalentInhibitors of T790M Double Mutants of EGFR” ACS Med. Chem. Lett., 7 (1),100-104 (2016); the crystal structure PDB 3IKA and related ligandsdescribed in Zhou, W. et al. “Novel mutant-selective EGFR kinaseinhibitors against EGFR T790M” Nature 462(7276), 1070-1074 (2009); thecrystal structure see PDB 5feq and related ligands described in Lelais,G., J. “Discovery of(R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor ofOncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for theTreatment of EGFR Mutant Non-Small-Cell Lung Cancers” Med. Chem., 59(14), 6671-6689 (2016); Lee, H.-J. “Noncovalent Wild-type-SparingInhibitors of EGFR T790M” Cancer Discov. 3(2): 168-181 (2013); thecrystal structure PDB 5j7h and related ligands described in Huang, W-S.et al. “Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing,Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.” J. Med.Chem. 59: 4948-4964 (2016); the crystal structure PDB 4vOg and relatedligands described in Hennessy, E. J. et al. “Utilization ofStructure-Based Design to Identify Novel, Irreversible Inhibitors ofEGFR Harboring the T790M Mutation.” ACS. Med. Chem. Lett. 7: 514-519(2016); the crystal structure PDB 5hg7 and related ligands described inCheng, H. “Discovery of1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one(PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor ofT790M-Containing EGFR Mutants.” J. Med. Chem. 59: 2005-2024 (2016); Hao,Y. “Discovery and Structural Optimization of N5-Substituted6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal GrowthFactor Receptor (EGFR) Inhibitors against L858R/T790M ResistanceMutation.” J. Med. Chem. 59: 7111-7124 (2016); the crystal structure PDB5ug8, 5ug9, and 5ugc and related ligands described in Planken, S.“Discovery ofN-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide(PF-06747775) through Structure-Based Drug Design: A High AffinityIrreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivityover Wild-Type EGFR.” J. Med. Chem. 60: 3002-3019 (2017); the crystalstructure PDB 5gnk and related ligands described in Wang, A. “Discoveryof(R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one(CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitorwith a Distinct Binding Mode.” J. Med. Chem. 60: 2944-2962 (2017); and,Juchum, M. “Trisubstituted imidazoles with a rigidized hinge bindingmotif act as single digit nM inhibitors of clinically relevant EGFRL858R/T790M and L858R/T790M/C797S mutants: An example of targethopping.” J. Med. Chem. DOI: 10.1021/acs.jmedchem.7b00178 (2017).

FIG. 8WW-8XX present examples of PAK1 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Rudolph, J. et al. “Chemically Diverse Group Ip21-Activated Kinase (PAK) Inhibitors Impart Acute CardiovascularToxicity with a Narrow Therapeutic Window.” J. Med. Chem. 59, 5520-5541(2016) and Karpov A S, et al. ACS Med Chem Lett. 22; 6(7):776-81 (2015).

FIG. 8YY presents examples of PAK4 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Staben S T, et al. J Med Chem. 13; 57(3): 1033-45(2014) and Guo, C. et al. “Discovery of pyrroloaminopyrazoles as novelPAK inhibitors” J. Med. Chem. 55, 4728-4739 (2012).

FIG. 8ZZ-8AAA present examples of IDO Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Yue, E. W.; et al. “Discovery of potentcompetitive inhibitors of indoleamine 2,3-dioxygenase with in vivopharmacodynamic activity and efficacy in a mouse melanoma model.” J.Med. Chem. 52, 7364-7367 (2009); Tojo, S.; et al. “Crystal structuresand structure, and activity relationships of imidazothiazole derivativesas IDO1 inhibitors.” ACS Med. Chem. Lett. 5, 1119-1123 (2014); Mautino,M. R. et al. “NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathwayinhibitor drug candidate for cancer therapy” Abstract 491, AACR 104thAnnual Meeting 2013; Apr. 6-10, 2013; Washington, D.C.; and,WO2012142237 titled “Fused imidazole derivatives useful as IDOinhibitors”.

FIG. 8BBB-8EEE present examples of ERK1 and ERK2 Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structures PDB 5K4I and5K4J and related ligands described in Blake, J. F. et al. “Discovery of(S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one(GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2)Inhibitor in Early Clinical Development” J. Med. Chem. 59: 5650-5660(2016); the crystal structure PDB 5BVF and related ligands described inBagdanoff, J. T. et al. “Tetrahydropyrrolo-diazepenones as inhibitors ofERK2 kinase” Bioorg. Med. Chem. Lett. 25, 3788-3792 (2015); the crystalstructure PDB 4QYY and related ligands described in Deng, Y. et al.“Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity SelectionScreening of an Inactive Kinase” J. Med. Chem. 57: 8817-8826 (2014); thecrystal structures PDB 5HD4 and 5HD7 and the related ligands describedin Jha, S. et al. “Dissecting Therapeutic Resistance to ERK Inhibition”Mol. Cancer Ther. 15: 548-559 (2016); the crystal structure PDB 4XJ0 andrelated ligands described in Ren, L. et al. “Discovery of highly potent,selective, and efficacious small molecule inhibitors of ERK1/2.” J. Med.Chem. 58: 1976-1991 (2015); the crystal structures PDB 4ZZM, 4ZZN, 4ZZOand related ligands described in Ward, R. A. et al. “Structure-GuidedDesign of Highly Selective and Potent Covalent Inhibitors of Erk1/2.” J.Med. Chem. 58: 4790 (2015); Burrows, F. et al. “KO-947, a potent ERKinhibitor with robust preclinical single agent activity in MAPK pathwaydysregulated tumors” Poster#5168, AACR National Meeting 2017; Bhagwat,S. V. et al. “Discovery of LY3214996, a selective and novel ERK1/2inhibitor with potent antitumor activities in cancer models with MAPKpathway alterations.” AACR National Meeting 2017; the crystal structuresPDB 3FHR and 3FXH and related ligands described in Cheng, R. et al.“High-resolution crystal structure of human Mapkap kinase 3 in complexwith a high affinity ligand” Protein Sci. 19: 168-173 (2010); thecrystal structures PDB 5NGU, 5NHF, 5NHH, 5NHJ, 5NHL, 5NHO, 5NHP, and5NHV and related ligands described in Ward, R. A. et al.“Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2from a Modestly Active and Promiscuous Chemical Start Point.” J. Med.Chem. 60, 3438-3450 (2017); and, the crystal structures PDB 3SHE and3R1N and related ligands described in Oubrie, A. et al. “Novel ATPcompetitive MK2 inhibitors with potent biochemical and cell-basedactivity throughout the series.” Bioorg. Med. Chem. Lett. 22: 613-618(2012).

FIG. 8FFF-8III present examples of ABL1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 1fpu and 2e2b andrelated ligands described in Schindler, T., et al. “Structural mechanismfor STI-571 inhibition of abelson tyrosine kinase”, Science 289:1938-1942 (2000); and Horio, T. et al. “Structural factors contributingto the Abl/Lyn dual inhibitory activity of 3-substituted benzamidederivatives”, Bioorg. Med. Chem. Lett. 17: 2712-2717 (2007); the crystalstructures PDB 2hzn and 2hiw and related ligands described inCowan-Jacob, S. W. et al. “Structural biology contributions to thediscovery of drugs to treat chronic myelogenous leukaemia”, ActaCrystallog. Sect. D 63: 80-93 (2007) and Okram, B. et al. “A generalstrategy for creating”, Chem. Biol. 13: 779-786 (2006); the crystalstructure PDB 3cs9 and related ligands described in Weisberg, E. et al.“Characterization of AMN107, a selective inhibitor of native and mutantBcr-Abl”, Cancer Cell 7: 129-14 (2005); the crystal structure PDB 3ik3and related ligands described in O'Hare, T. et al. “AP24534, apan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibitsthe T315I mutant and overcomes mutation-based resistance”, Cancer Cell16: 401-412 (2009); the crystal structure PDB 3mss and related ligandsdescribed in Jahnke, W. et al. “Binding or bending: distinction ofallosteric Abl kinase agonists from antagonists by an NMR-basedconformational assay”, J. Am. Chem. Soc. 132: 7043-7048 (2010); thecrystal structure PDB 3oy3 and related ligands described in Zhou, T. etal. “Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib(AP24534): Lessons for Overcoming Kinase Inhibitor Resistance”, Chem.Biol. Drug Des. 77: 1-11 (2011); the crystal structures PDB 3qri and3qrk and related ligands described in Chan, W. W. et al. “ConformationalControl Inhibition of the BCR-ABL1 Tyrosine Kinase, Including theGatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036”,Cancer Cell 19: 556-568 (2011); the crystal structure PDB 5hu9 and 2f4jand related ligands described in Liu, F. et al. “Discovery andcharacterization of a novel potent type II native and mutant BCR-ABLinhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)”, Oncotarget 7:45562-45574 (2016) and Young, M. A. et al. “Structure of the kinasedomain of an imatinib-resistant Abl mutant in complex with the Aurorakinase inhibitor VX-680”, Cancer Res. 66: 1007-1014 (2006); the crystalstructure PDB 2gqg and 2qoh and related ligands described in Tokarski,J. S. et al. “The Structure of Dasatinib (BMS-354825) Bound to ActivatedABL Kinase Domain Elucidates Its Inhibitory Activity againstImatinib-Resistant ABL Mutants”, Cancer Res. 66: 5790-5797 (2006); andZhou, T. et al. “Crystal Structure of the T315I Mutant of Abl Kinase”,Chem. Biol. Drug Des. 70: 171-181 (2007); the crystal structure PDB 2gqgand 2qoh and related ligands described in Tokarski, J. S. et al. “TheStructure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase DomainElucidates Its Inhibitory Activity against Imatinib-Resistant ABLMutants”, Cancer Res. 66: 5790-5797 (2006) and Zhou, T. et al. “CrystalStructure of the T315I Mutant of Abl Kinase”, Chem. Biol. Drug Des. 70:171-181 (2007); the crystal structure PDB 2gqg and 2qoh and relatedligands described in Tokarski, J. S. et al. “The Structure of Dasatinib(BMS-354825) Bound to Activated ABL Kinase Domain Elucidates ItsInhibitory Activity against Imatinib-Resistant ABL Mutants”, Cancer Res.66: 5790-5797 (2006) and Zhou, T. et al. “Crystal Structure of the T315IMutant of Abl Kinase”, Chem. Biol. Drug Des. 70: 171-181 (2007); thecrystal structures PDB 3dk3 and 3dk8 and related ligands described inBerkholz, D. S. et al. “Catalytic cycle of human glutathione reductasenear 1 A resolution” J. Mol. Biol. 382: 371-384 (2008); the crystalstructure PDB 3ue4 and related ligands described in Levinson, N. M. etal. “Structural and spectroscopic analysis of the kinase inhibitorbosutinib and an isomer of bosutinib binding to the abl tyrosine kinasedomain”, Plos One 7: e29828-e29828 (2012); the crystal structure PDB4cy8 and related ligands described in Jensen, C. N. et al. “Structuresof the Apo and Fad-Bound Forms of 2-Hydroxybiphenyl 3-Monooxygenase(Hbpa) Locate Activity Hotspots Identified by Using Directed Evolution”,Chembiochem 16: 968 (2015); the crystal structure PDB 2hz0 and relatedligands described in Cowan-Jacob, S. W. et al. “Structural biologycontributions to the discovery of drugs to treat chronic myelogenousleukaemia”, Acta Crystallogr D Biol Crystallogr. 63(Pt 1):80-93 (2007);the crystal structure PDB 3pyy and related ligands described in Yang, J.et al. “Discovery and Characterization of a Cell-Permeable,Small-Molecule c-Abl Kinase Activator that Binds to the MyristoylBinding Site”, Chem. Biol. 18: 177-186 (2011); and, the crystalstructure PDB 5k5v and related ligands described in Kim, M. K., et al.“Structural basis for dual specificity of yeast N-terminal amidase inthe N-end rule pathway”, Proc. Natl. Acad. Sci. U.S.A. 113: 12438-12443(2016).

FIG. 8JJJ presents examples of ABL2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 2xyn and related ligandsdescribed in Salah, E. et al. “Crystal Structures of Abl-Related Gene(Abl2) in Complex with Imatinib, Tozasertib (Vx-680), and a Type IInhibitor of the Triazole Carbothioamide Class”, J. Med. Chem. 54: 2359(2011); the crystal structure PDB 4xli and related ligands described inHa, B. H. et al. “Structure of the ABL2/ARG kinase in complex withdasatinib” Acta Crystallogr. Sect. F 71: 443-448 (2015); and the crystalstructure PDB 3gvu and related ligands described in Salah, E. et al.“The crystal structure of human ABL2 in complex with Gleevec”, to bepublished.

FIG. 8KKK-8MMM present examples of AKT1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, Lippa, B. et al. “Synthesis and structure basedoptimization of novel Akt inhibitors Bioorg. Med. Chem. Lett. 18:3359-3363 (2008); Freeman-Cook, K. D. et al. “Design of selective,ATP-competitive inhibitors of Akt”, J. Med. Chem. 53: 4615-4622 (2010);Blake, J. F. et al “Discovery of pyrrolopyrimidine inhibitors of Akt”,Bioorg. Med. Chem. Lett. 20: 5607-5612 (2010); Kallan, N.C. et al.“Discovery and SAR of spirochromane Akt inhibitors”, Bioorg. Med. Chem.Lett. 21: 2410-2414 (2011); Lin, K “An ATP-Site On-Off Switch ThatRestricts Phosphatase Accessibility of Akt”, Sci. Signal. 5: ra37-ra37(2012); Addie, M. et al. “Discovery of4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide(AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases”, J.Med. Chem. 56: 2059-2073 (2013); Wu, W. I., et al. “Crystal structure ofhuman AKT1 with an allosteric inhibitor reveals a new mode of kinaseinhibition. Plos One 5: 12913-12913 (2010); Ashwell, M. A. et al.“Discovery and optimization of a series of3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orallybioavailable, selective, and potent ATP-independent Akt inhibitors”, J.Med. Chem. 55: 5291-5310 (2012); and, Lapierre, J. M. et al. “Discoveryof3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine(ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKTInhibitor”, J. Med. Chem. 59: 6455-6469 (2016).

FIG. 8NNN-8OOO present examples of AKT2 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structured PDB 2jdo and 2jdr andrelated ligands described in Davies, T. G. et al. “A StructuralComparison of Inhibitor Binding to Pkb, Pka and Pka-Pkb Chimera”, J.Mol. Biol. 367: 882 (2007); the crystal structure PDB 2uw9 and relatedligands described in Saxty, G. et al “Identification of Inhibitors ofProtein Kinase B Using Fragment-Based Lead Discovery”, J. Med Chem. 50:2293-2296 (2007); the crystal structure PDB 2x39 and 2xh5 and relatedligands described in Mchardy, T. et al. “Discovery of4-Amino-1-(7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl)Piperidine-4-Carboxamides asSelective, Orally Active Inhibitors of Protein Kinase B (Akt)”, J. Med.Chem. 53: 2239d (2010); the crystal structure PDB 3d03 and relatedligands described in Hadler, K. S. et al. “Substrate-promoted formationof a catalytically competent binuclear center and regulation ofreactivity in a glycerophosphodiesterase from Enterobacter aerogenes’,J. Am. Chem. Soc. 130: 14129-14138 (2008); and, the crystal structuresPDB 3e87, 3e8d and 3e88 and related ligands described in Rouse, M. B. etal. “Aminofurazans as potent inhibitors of AKT kinase” Bioorg. Med.Chem. Lett. 19: 1508-1511 (2009).

FIG. 8PPP presents examples of BMX Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 3sxr and 3sxr andrelated ligands described in Muckelbauer, J. et al. “X-ray crystalstructure of bone marrow kinase in the x chromosome: a Tec familykinase”, Chem. Biol. Drug Des. 78: 739-748 (2011).

FIG. 8QQQ-8SSS present examples of CSF1R Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 2i0v and 2i1m andrelated ligands described in Schubert, C. et al. “Crystal structure ofthe tyrosine kinase domain of colony-stimulating factor-1 receptor(cFMS) in complex with two inhibitors”, J. Biol. Chem. 282: 4094-4101(2007); the crystal structure PDB 3bea and related ligands described inHuang, H. et al. “Design and synthesis of a pyrido[2,3-d]pyrimidin-5-oneclass of anti-inflammatory FMS inhibitors”, Bioorg. Med. Chem. Lett. 18:2355-2361 (2008); the crystal structure PDB 3dpk and related ligandsdescribed in M. T., McKay, D. B. Overgaard, “Structure of the Elastaseof Pseudomonas aeruginosa Complexed with Phosphoramidon”, to bepublished; the crystal structures PDB 3krj and 3krl and related ligandsdescribed in Illig, C. R. et al. “Optimization of a Potent Class ofArylamide Colony-Stimulating Factor-1 Receptor Inhibitors Leading toAnti-inflammatory Clinical Candidate4-Cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide(JNJ-28312141”, J. Med. Chem. 54: 7860-7883 (2011); the crystalstructure PDB 4r7h and related ligands described in Tap, W. D. et al.“Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-CellTumor, N Engl J Med 373: 428-437 (2015); the crystal structure PDB 31cdand 31coa and related ligands described in Meyers, M. J. et al.“Structure-based drug design enables conversion of a DFG-in bindingCSF-1R kinase inhibitor to a DFG-out binding mod”, Bioorg. Med. Chem.Lett. 20: 1543-1547 (2010); the crystal structure PDB 4hw7 and relatedligands described in Zhang, C. et al. “Design and pharmacology of ahighly specific dual FMS and KIT kinase inhibitor”, Proc. Natl. Acad.Sci. USA 110: 5689-5694 (2013); and, the crystal structure PDB 4r7i andrelated ligands described in Tap, W. D. et al. “Structure-GuidedBlockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor”, N Engl J Med373: 428-437 (2015).

FIG. 8TTT presents examples of CSK Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Levinson, N. M. et al. “Structural basis for therecognition of c-Src by its inactivator Csk”, Cell 134: 124-134 (2008).

FIG. 8UUU-8YYY present examples of DDR1 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 3zos and 4bkj andrelated ligands described in Canning, P. et al. “Structural MechanismsDetermining Inhibition of the Collagen Receptor Ddr1 by Selective andMulti-Targeted Type II Kinase Inhibitors”, J. Mol. Biol. 426: 2457(2014); the crystal structure PDB 4ckr and related ligands described inKim, H. et al. “Discovery of a Potent and Selective Ddr1 ReceptorTyrosine Kinase Inhibitor”, ACS Chem. Biol. 8: 2145 (2013); the crystalstructure PDB 5bvk, 5bvn and 5bvw and related ligands described inMurray, C. W et al. “Fragment-Based Discovery of Potent and SelectiveDDR1/2 Inhibitors”, ACS Med. Chem. Lett. 6: 798-803 (2015); the crystalstructure PDB 5fdp and related ligands described in Wang, Z. et al.“Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides asSelective Discoidin Domain Receptor 1 (DDR1) Inhibitors”, J. Med. Chem.59: 5911-5916 (2016); and, the crystal structure PDB 5fdx and relatedligands described in Bartual, S. G. et al. “Structure of DDR1 receptortyrosine kinase in complex with D2164 inhibitor at 2.65 Angstromsresolution”, to be published.

FIG. 8ZZZ-8CCCC present examples of EPHA2 Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structures PDB 5i9x, 5i9y, 5ia0 and5ia1 and related ligands described in Heinzlmeir, S. et al. “ChemicalProteomics and Structural Biology Define EPHA2 Inhibition by ClinicalKinase Drug”, ACS Chem. Biol. 11: 3400-3411 (2016); the crystalstructure PDB 5i9z and related ligands described in Heinzlmeir, S. etal. “Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase withdanusertib (PHA739358)”, ACS Chem Biol 11 3400-3411 (2016); and, thecrystal structures PDB 5ia2, 5ia3, 5ia4, and 5ia5 and related ligandsdescribed in Heinzlmeir, S. et al. “Chemical Proteomics and StructuralBiology Define EPHA2 Inhibition by Clinical Kinase Drug”, ACS Chem.Biol. 11: 3400-3411 (2016).

FIG. 8DDDD-8FFFF present examples of EPHA3 Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the crystal structure PDB 4g2f and relatedligands described in Zhao, H. et al. “Discovery of a novel chemotype oftyrosine kinase inhibitors by fragment-based docking and moleculardynamics”, ACS Med. Chem. Lett. 3: 834-838 (2012); the crystal structurePDB 4gk2 and 4gk3 and related ligands described in Lafleur, K. et al.“Optimization of Inhibitors of the Tyrosine Kinase EphB4. 2. CellularPotency Improvement and Binding Mode Validation by X-rayCrystallography”, J. Med. Chem. 56: 84-96 (2013); the crystal structurePDB 4gk3 and related ligands described in Lafleur, K. et al.“Optimization of Inhibitors of the Tyrosine Kinase EphB4. 2. CellularPotency Improvement and Binding Mode Validation by X-rayCrystallography”, J. Med. Chem. 56: 84-96 (2013); the crystal structurePDB 4p4c and 4p5q and related ligands described in Unzue, A. et al.“Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1/2 and II Eph TyrosineKinase Inhibitors: Structure-Based Design, Synthesis, and in VivoValidation”, J. Med. Chem. 57: 6834-6844 (2014); the crystal structurePDB 4p5z and related ligands described in Unzue, A. et al.“Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1/2 and II Eph TyrosineKinase Inhibitors: Structure-Based Design, Synthesis, and in VivoValidation”, J. Med. Chem. 57: 6834-6844 (2014); the crystal structurePDB 4twn and related ligands described in Dong, J. et al. “StructuralAnalysis of the Binding of Type I, I1/2, and II Inhibitors to EphTyrosine Kinases”, ACS Med. Chem. Lett. 6: 79-83 (2015); the crystalstructure PDB 3dzq and related ligands described in Walker, J. R.“Kinase Domain of Human Ephrin Type-A Receptor 3 (Epha3) in Complex withALW-II-38-3”, to be published.

FIG. 8GGGG presents examples of EPHA4 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 2y60 and related ligandsdescribed in Clifton, I. J. et al. “The Crystal Structure ofIsopenicillin N Synthase withDelta((L)-Alpha-Aminoadipoyl)-(L)-Cysteinyl-(D)-Methionine RevealsThioether Coordination to Iron”, Arch. Biochem. Biophys. 516: 103 (2011)and the crystal structure PDB 2xyu and related ligands described in VanLinden, O. P et al. “Fragment Based Lead Discovery of Small MoleculeInhibitors for the Epha4 Receptor Tyrosine Kinase”, Eur. J. Med. Chem.47: 493 (2012).

FIG. 8HHHH presents examples of EPHA7 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 3dko and related ligandsdescribed in Walker, J. R. et al. “Kinase domain of human ephrin type-areceptor 7 (epha7) in complex with ALW-II-49-7”, to be published.

FIG. 8IIII-8LLLL presents examples of EPHB4 Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the crystal structure PDB 2vxl and relatedligands described in Bardelle, C. et al. “Inhibitors of the TyrosineKinase Ephb4. Part 2: Structure-Based Discovery and Optimisation of3,5-Bis Substituted Anilinopyrimidines”, Bioorg. Med. Chem. Lett. 18:5717 (2008); the crystal structure PDB 2x9f and related ligandsdescribed in Bardelle, C. et al. “Inhibitors of the Tyrosine KinaseEphb4. Part 3: Identification of Non-Benzodioxole-Based KinaseInhibitors”, Bioorg. Med. Chem. Lett. 20: 6242-6245 (2010); the crystalstructure PDB 2xvd and related ligands described in Barlaam, B. et al.“Inhibitors of the Tyrosine Kinase Ephb4. Part 4: Discovery andOptimization of a Benzylic Alcohol Series”, Bioorg. Med. Chem. Lett. 21:2207 (2011); the crystal structure PDB 3zew and related ligandsdescribed in Overman, R. C. et al. “Completing the Structural FamilyPortrait of the Human Ephb Tyrosine Kinase Domains”, Protein Sci. 23:627 (2014); the crystal structure PDB 4aw5 and related ligands describedin Kim, M. H. et al. “The Design, Synthesis, and Biological Evaluationof Potent Receptor Tyrosine Kinase Inhibitors”, Bioorg. Med. Chem. Lett.22: 4979 (2012); the crystal structure PDB 4bb4 and related ligandsdescribed in Vasbinder, M. M. et al. “Discovery and Optimization of aNovel Series of Potent Mutant B-Raf V600E Selective Kinase Inhibitors”J. Med. Chem. 56: 1996.”, (2013); the crystal structures PDB 2vwu, 2vwvand 2vww and related ligands described in Bardelle, C. et al “Inhibitorsof the Tyrosine Kinase Ephb4. Part 1: Structure-Based Design andOptimization of a Series of 2,4-Bis-Anilinopyrimidines”, Bioorg. Med.Chem. Lett. 18: 2776-2780 (2008); the crystal structures PDB 2vwx, 2vwy,and 2vwz and related ligands described in Bardelle, C. et al.“Inhibitors of the Tyrosine Kinase Ephb4. Part 2: Structure-BasedDiscovery and Optimisation of 3,5-Bis Substituted Anilinopyrimidines”,Bioorg. Med. Chem. Lett. 18: 5717 (2008); and, the crystal structure PDB2vxo and related ligands described in Welin, M. et al. “SubstrateSpecificity and Oligomerization of Human Gmp Synthetas”, J. Mol. Biol.425: 4323 (2013).

FIG. 8MMMM presents examples of ERBB2 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure and related ligandsdescribed in Aertgeerts, K. et al “Structural Analysis of the Mechanismof Inhibition and Allosteric Activation of the Kinase Domain of HER2Protein”, J. Biol. Chem. 286: 18756-18765 (2011) and the crystalstructure and related ligands described in Ishikawa, T. et al. “Designand Synthesis of Novel Human Epidermal Growth Factor Receptor 2(HER2)/Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing aPyrrolo[3,2-d]pyrimidine Scaffold” J. Med. Chem. 54: 8030-8050 (2011).

FIG. 8NNNN presents examples of ERBB3 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Littlefield, P. et al. “An ATP-CompetitiveInhibitor Modulates the Allosteric Function of the HER3 Pseudokinase”,Chem. Biol. 21: 453-458 (2014).

FIG. 8OOOO presents examples ERBB4 Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Qiu, C. et al. “Mechanism of Activation andInhibition of the HER4/ErbB4 Kinase”, Structure 16: 460-467 (2008) andWood, E. R. et al. “6-Ethynylthieno[3,2-d]- and6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiersof ErbB kinases”, Proc. Natl. Acad. Sci. Usa 105: 2773-2778 (2008).

FIG. 8PPPP-8QQQQ present examples of FES Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, Filippakopoulos, P. et al “Structural Coupling ofSH2-Kinase Domains Links Fes and Abl Substrate Recognition and KinaseActivation.” Cell 134: 793-803 (2008) and Hellwig, S. et al.“Small-Molecule Inhibitors of the c-Fes Protein-Tyrosine Kinase”, Chem.Biol. 19: 529-540 (2012).

FIG. 8RRRR presents examples of FYN Targeting Ligands wherein R is thepoint at which the Linker is attached. For additional examples andrelated ligands, see, Kinoshita, T. et. al. “Structure of human Fynkinase domain complexed with staurosporine”, Biochem. Biophys. Res.Commun. 346: 840-844 (2006).

FIG. 8SSSS-8VVVV present examples of GSG2 (Haspin) Targeting Ligandswherein R is the point at which the Linker is attached. For additionalexamples and related ligands, see, the crystal structures PDB 3e7v, PDB3f2n, 3fmd and related ligands described in Filippakopoulos, P. et al.“Crystal Structure of Human Haspin with a pyrazolo-pyrimidine ligand”,to be published; the crystal structure PDB 3iq7 and related ligandsdescribed in Eswaran, J. et al. “Structure and functionalcharacterization of the atypical human kinase haspin”, Proc. Natl. Acad.Sci. USA 106: 20198-20203 (2009); and, the crystal structure PDB 4qtcand related ligands described in Chaikuad, A. et al. “A unique inhibitorbinding site in ERK1/2 is associated with slow binding kinetics”, Nat.Chem. Biol. 10: 853-860 (2014).

FIG. 8WWWW-8AAAAA present examples of HCK Targeting Ligands wherein R isthe point at which the Linker is attached. For additional examples andrelated ligands, see, the crystal structure PDB 1qcf and related ligandsdescribed in Schindler, T. et al. “Crystal structure of Hck in complexwith a Src family-selective tyrosine kinase inhibitor”, Mol. Cell 3:639-648 (1999); the crystal structure PDB 2c0i and 2c0t and relatedligands described in Burchat, A. et al. “Discovery of A-770041, aSrc-Family Selective Orally Active Lck Inhibitor that Prevents OrganAllograft Rejection”, Bioorg. Med. Chem. Lett. 16: 118 (2006); thecrystal structure PDB 2hk5 and related ligands described in Sabat, M. etal. “The development of 2-benzimidazole substituted pyrimidine basedinhibitors of lymphocyte specific kinase (Lck)”, Bioorg. Med. Chem.Lett. 16: 5973-5977 (2006); the crystal structures PDB 3vry, 3vs3, 3vs6,and 3vs7 and related ligands described in Saito, Y. et al. “APyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells inVivo”, Sci Transl Med 5: 181ra52-181ra52 (2013); and, the crystalstructure PDB 41ud and related ligands described in Parker, L. J. et al“Kinase crystal identification and ATP-competitive inhibitor screeningusing the fluorescent ligand SKF86002”, Acta Crystallogr., Sect. D 70:392-404 (2014).

FIG. 8BBBBB-8FFFFF present examples of IGF1R Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the crystal structure PDB 2oj9 and relatedligands described in Velaparthi, U. et al. “Discovery and initial SAR of3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-ones as inhibitors ofinsulin-like growth factor 1-receptor (IGF-1R)”, Bioorg. Med. Chem.Lett. 17: 2317-2321 (2007); the crystal structure PDB 3i81 and relatedligands described in Wittman, M. D. et al. “Discovery of a2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807)of insulin-like growth factor receptor (IGF-1R) kinase in clinicaldevelopment.”, J. Med. Chem. 52: 7360-7363 (2009); the crystal structurePDB 3nw5 and related ligands described in Sampognaro, A. J. et al.“Proline isosteres in a series of 2,4-disubstitutedpyrrolo[1,2-f][1,2,4]triazine inhibitors of IGF-1R kinase and IRkinase”, Bioorg. Med. Chem. Lett. 20: 5027-5030 (2010); the crystalstructure PDB 3qqu and related ligands described in Buchanan, J. L. etal. “Discovery of 2,4-bis-arylamino-1,3-pyrimidines as insulin-likegrowth factor-1 receptor (IGF-1R) inhibitors”, Bioorg. Med. Chem. Lett.21: 2394-2399 (2011); the crystal structure PDB 4d2r and related ligandsdescribed in Kettle, J. G. et al. “Discovery and Optimization of a NovelSeries of Dyrk1B Kinase Inhibitors to Explore a Mek ResistanceHypothesis”. J. Med. Chem. 58: 2834 (2015); the crystal structure PDB3fxq and related ligands described in Monferrer, D. et al. “Structuralstudies on the full-length LysR-type regulator TsaR from Comamonastestosteroni T-2 reveal a novel open conformation of the tetrameric LTTRfold”, Mol. Microbiol. 75: 1199-1214 (2010); the crystal structure PDB5fxs and related ligands described in Degorce, S. et al. “Discovery ofAzd9362, a Potent Selective Orally Bioavailable and Efficacious NovelInhibitor of Igf-R1”, to be published; the crystal structure PDB 2zm3and related ligands described in Mayer, S. C. et al. “Leadidentification to generate isoquinolinedione inhibitors of insulin-likegrowth factor receptor (IGF-1R) for potential use in cancer treatment”,Bioorg. Med. Chem. Lett. 18: 3641-3645 (2008); the crystal structure PDB3f5p and related ligands described in “Lead identification to generate3-cyanoquinoline inhibitors of insulin-like growth factor receptor(IGF-1R) for potential use in cancer treatment” Bioorg. Med. Chem. Lett.19: 62-66 (2009); the crystal structure PDB 31vp and related ligandsdescribed in Nemecek, C. et al. “Design of Potent IGF1-R InhibitorsRelated to Bis-azaindoles” Chem. Biol. Drug Des. 76: 100-106 (2010); thecrystal structure PDB 3o23 and related ligands described in Lesuisse, D.et al. “Discovery of the first non-ATP competitive IGF-1R kinaseinhibitors: Advantages in comparison with competitive inhibitors”,Bioorg. Med. Chem. Lett. 21: 2224-2228 (2011); the crystal structure PDB3d94 and related ligands described in Wu, J. et al. “Small-moleculeinhibition and activation-loop trans-phosphorylation of the IGF1receptor”, Embo J. 27: 1985-1994 (2008); and, the crystal structure PDB5hzn and related ligands described in Stauffer, F. et al.“Identification of a5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidineseries of IGF-1R inhibitors”, Bioorg. Med. Chem. Lett. 26: 2065-2067(2016).

FIG. 8GGGGG-8JJJJJ present examples of INSR Targeting Ligands wherein Ris the point at which the Linker is attached. For additional examplesand related ligands, see, the crystal structure PDB 2z8c and relatedligands described in Katayama, N. et al. “Identification of a keyelement for hydrogen-bonding patterns between protein kinases and theirinhibitors”, Proteins 73: 795-801 (2008); the crystal structure PDB 3ekkand related ligands described in Chamberlain, S. D. et al. “Discovery of4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: Potent inhibitors of theIGF-1R receptor tyrosine kinase”, (2009) Bioorg. Med. Chem. Lett. 19:469-473; the crystal structure PDB 3ekn and related ligands described inChamberlain, S. D. et al. “Optimization of4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinaseinhibitors towards JNK selectivity”, Bioorg. Med. Chem. Lett. 19:360-364 (2009); the crystal structure PDB 5els and related ligandsdescribed in Sanderson, M. P. et al. “BI 885578, a Novel IGF1R/INSRTyrosine Kinase Inhibitor with Pharmacokinetic Properties ThatDissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis”Mol. Cancer Ther. 14: 2762-2772 ”, (2015); the crystal structure PDB3eta and related ligands described in Patnaik, S. et al. “Discovery of3,5-disubstituted-1H-pyrrolo[2,3-b]pyridines as potent inhibitors of theinsulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase”, Bioorg.Med. Chem. Lett. 19: 3136-3140 (2009); the crystal structure PDB 5hhwand related ligands described in Stauffer, F. et al. “Identification ofa5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidineseries of IGF-1R inhibitors”, Bioorg. Med. Chem. Lett. 26: 2065-2067(2016); and, the crystal structure PDB 4ibm and related ligandsdescribed in Anastassiadis, T. et al. “A highly selective dual insulinreceptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitorderived from an extracellular signal-regulated kinase (ERK) inhibitor”,J. Biol. Chem. 288: 28068-28077 (2013).

FIG. 8KKKKK-8PPPPP present examples of HBV Targeting Ligands wherein Ris the point at which the Linker is attached, Y is methyl or isopropyl,and X is N or C. For additional examples and related ligands, see,Weber, O.; et al. “Inhibition of human hepatitis B virus (HBV) by anovel non-nucleosidic compound in a transgenic mouse model.” AntiviralRes. 54, 69-78 (2002); Deres, K.; et al. “Inhibition of hepatitis Bvirus replication by drug-induced depletion of nucleocapsids.” Science,299, 893-896 (2003); Stray, S. J.; Zlotnick, A. “BAY 41-4109 hasmultiple effects on Hepatitis B virus capsid assembly.” J. Mol.Recognit. 19, 542-548 (2006); Stray, S. J.; et al.“heteroaryldihydropyrimidine activates and can misdirect hepatitis Bvirus capsid assembly.” Proc. Natl. Acad. Sci. U.S.A, 102, 8138-8143(2005); Guan, H.; et al. “The novel compound Z060228 inhibits assemblyof the HBV capsid.” Life Sci. 133, 1-7 (2015); Wang, X. Y.; et al. “Invitro inhibition of HBV replication by a novel compound, GLS4, and itsefficacy against adefovir-dipivoxil-resistant HBV mutations.” AntiviralTher. 17, 793-803 (2012); Klumpp, K.; et al. “High-resolution crystalstructure of a hepatitis B virus replication inhibitor bound to theviral core protein.” 112, 15196-15201 (2015); Qiu, Z.; et al. “Designand synthesis of orally bioavailable 4-methylheteroaryldihydropyrimidine based hepatitis B virus (HBV) capsidinhibitors.” J. Med. Chem. 59, 7651-7666 (2016); Zhu, X.; et al.“2,4-Diaryl-4,6,7,8-tetrahydroquinazolin-5(1H)-one derivatives asanti-HBV agents targeting at capsid assembly.” Bioorg. Med. Chem. Lett.20, 299-301 (2010); Campagna, M. R.; et al. “Sulfamoylbenzamidederivatives inhibit the assembly of hepatitis B virus nucleocapsids.” J.Virol. 87, 6931-6942 (2013); Campagna, M. R.; et al. “Sulfamoylbenzamidederivatives inhibit the assembly of hepatitis B virus nucleocapsids.” J.Virol. 87, 6931-6942 (2013); WO 2013096744 A1 titled “Hepatitis Bantivial agents”; WO 2015138895 titled “Hepatitis B core proteinallosteric modulators”; Wang, Y. J.; et al. “A novel pyridazinonederivative inhibits hepatitis B virus replication by inducinggenome-free capsid formation.” Antimicrob. Agents Chemother. 59,7061-7072 (2015); WO 2014033167 titled “Fused bicyclic sulfamoylderivatives for the treatment of hepatitis”; U.S. 20150132258 titled“Azepane derivatives and methods of treating hepatitis B infections”;and, WO 2015057945 “Hepatitis B viral assembly effector”.

FIG. 9 is a dendrogram of the human bromodomain family of proteinsorganized into eightsubfamilies, which are involved in epigeneticsignaling and chromatin biology. Any of the proteins of the bromodomainfamily in FIG. 9 can be selected as a Target Protein according to thepresent invention.

DETAILED DESCRIPTION I. Definitions

Compounds are described using standard nomenclature. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The compounds in any of the Formulas described herein may be in the formof a racemate, enantiomer, mixture of enantiomers, diastereomer, mixtureof diastereomers, tautomer, N-oxide, isomer; such as rotamer, as if eachis specifically described unless specifically excluded by context.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. Recitation of ranges of values are merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The endpoints of all rangesare included within the range and independently combinable. All methodsdescribed herein can be performed in a suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof examples, or exemplary language (e.g., “such as”), is intended merelyto better illustrate the invention and does not pose a limitation on thescope of the invention unless otherwise claimed.

The present invention includes compounds of Formula I, Formula II,Formula III, and Formula IV with at least one desired isotopicsubstitution of an atom, at an amount above the natural abundance of theisotope, i.e., enriched. Isotopes are atoms having the same atomicnumber but different mass numbers, i.e., the same number of protons buta different number of neutrons.

Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine and iodine such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, and ¹²⁵I respectively. In onenon-limiting embodiment, isotopically labelled compounds can be used inmetabolic studies (with, for example ¹⁴C), reaction kinetic studies(with, for example ²H or ³H), detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays, or in radioactive treatment of patients. In particular, an ¹⁸Flabeled compound may be particularly desirable for PET or SPECT studies.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 90, 95 or 99% or more enriched in an isotope at any locationof interest. In one non-limiting embodiment, deuterium is 90, 95 or 99%enriched at a desired location.

In one non-limiting embodiment, the substitution of a hydrogen atom fora deuterium atom can be provided in any compound of Formula I, FormulaII, Formula III, or Formula IV. In one non-limiting embodiment, thesubstitution of a hydrogen atom for a deuterium atom occurs within oneor more groups selected from any of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹¹, R¹², R¹³, R¹⁴ R¹⁵, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸,R¹⁰¹, Linker, and Targeting Ligand. For example, when any of the groupsare, or contain for example through substitution, methyl, ethyl, ormethoxy, the alkyl residue may be deuterated (in non-limitingembodiments, CDH₂, CD₂H, CD₃, CH₂CD₃, CD₂CD₃, CHDCH₂D, CH₂CD₃, CHDCHD₂,OCDH₂, OCD₂H, or OCD₃ etc.). In certain other embodiments, when twosubstituents are combined to form a cycle the unsubstituted carbons maybe deuterated.

The compound of the present invention may form a solvate with a solvent(including water). Therefore, in one non-limiting embodiment, theinvention includes a solvated form of the compound. The term “solvate”refers to a molecular complex of a compound of the present invention(including a salt thereof) with one or more solvent molecules.Non-limiting examples of solvents are water, ethanol, isopropanol,dimethyl sulfoxide, acetone and other common organic solvents. The term“hydrate” refers to a molecular complex comprising a compound of theinvention and water. Pharmaceutically acceptable solvates in accordancewith the invention include those wherein the solvent may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO. A solvate can be in a liquidor solid form.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —(C═O)NH₂is attached through carbon of the carbonyl (C═O) group.

“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbongroup. In one non-limiting embodiment, the alkyl group contains from 1to about 12 carbon atoms, more generally from 1 to about 6 carbon atomsor from 1 to about 4 carbon atoms. In one non-limiting embodiment, thealkyl contains from 1 to about 8 carbon atoms. In certain embodiments,the alkyl is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, or C₁-C₆. The specified rangesas used herein indicate an alkyl group having each member of the rangedescribed as an independent species. For example, the term C₁-C₆ alkylas used herein indicates a straight or branched alkyl group having from1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each ofthese is described as an independent species and therefore each subsetis considered separately disclosed. For example, the term C₁-C₄ alkyl asused herein indicates a straight or branched alkyl group having from 1,2, 3, or 4 carbon atoms and is intended to mean that each of these isdescribed as an independent species. Examples of alkyl include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl,n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and2,3-dimethylbutane. In an alternative embodiment, the alkyl group isoptionally substituted. The term “alkyl” also encompasses cycloalkyl orcarbocyclic groups. For example, when a term is used that includes “alk”then “cycloalkyl” or “carbocyclic” can be considered part of thedefinition, unless unambiguously excluded by the context. For exampleand without limitation, the terms alkyl, alkoxy, haloalkyl, etc. can allbe considered to include the cyclic forms of alkyl, unless unambiguouslyexcluded by context.

“Alkenyl” is a linear or branched aliphatic hydrocarbon groups havingone or more carbon-carbon double bonds that may occur at a stable pointalong the chain. The specified ranges as used herein indicate an alkenylgroup having each member of the range described as an independentspecies, as described above for the alkyl moiety. Examples of alkenylradicals include, but are not limited to ethenyl, propenyl, allyl,propenyl, butenyl and 4-methylbutenyl. The term “alkenyl” also embodies“cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z”alkenyl geometry. In an alternative embodiment, the alkenyl group isoptionally substituted. The term “Alkenyl” also encompasses cycloalkylor carbocyclic groups possessing at least one point of unsaturation.

“Alkynyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon triple bonds that may occur at anystable point along the chain. The specified ranges as used hereinindicate an alkynyl group having each member of the range described asan independent species, as described above for the alkyl moiety.Examples of alkynyl include, but are not limited to, ethynyl, propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. Inan alternative embodiment, the alkynyl group is optionally substituted.The term “Alkynyl” also encompasses cycloalkyl or carbocyclic groupspossessing at least one triple bond.

“Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example,can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6 carbon moiety,or an indicated number of carbon atoms, for example C₁-C₂alkylene,C₁-C₃alkylene, C₁-C₄alkylene, C₁-C₆alkylene, or C₁-C₆alkylene.

“Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbondouble bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2to 6 carbon moiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkenylene.

“Alkynylene” is a bivalent hydrocarbon having at least one carbon-carbontriple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, 2to 6 carbon moiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkynylene.

“Halo” and “Halogen” refers to fluorine, chlorine, bromine or iodine.

“Haloalkyl” is a branched or straight-chain alkyl groupssubstituted with1 or more halo atoms described above, up to the maximum allowable numberof halogen atoms. Examples of haloalkyl groups include, but are notlimited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perhaloalkyl” meansan alkyl group having all hydrogen atoms replaced with halogen atoms.Examples include but are not limited to, trifluoromethyl andpentafluoroethyl.

“Chain” indicates a linear chain to which all other chains, long orshort or both, may be regarded as being pendant. Where two or morechains could equally be considered to be the main chain, “chain” refersto the one which leads to the simplest representation of the molecule.

“Haloalkoxy” indicates a haloalkyl group as defined herein attachedthrough an oxygen bridge (oxygen of an alcohol radical).

“Heterocycloalkyl” is an alkyl group as defined herein substituted witha heterocyclo group as defined herein.

“Arylalkyl” is an alkyl group as defined herein substituted with an arylgroup as defined herein.

“Heteroarylalkyl” is an alkyl group as defined herein substituted with aheteroaryl group as defined herein.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbonatoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems whereinthe aryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the radical or point of attachment is onthe aryl ring, and in such instances, the number of carbon atomscontinue to designate the number of carbon atoms in the aryl ringsystem. The one or more fused carbocyclyl or heterocyclyl groups can be4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclylor heterocyclyl groups that optionally contain 1, 2, or 3 heteroatomsindependently selected from nitrogen, oxygen, phosphorus, sulfur,silicon and boron, to form, for example, a 3,4-methylenedioxyphenylgroup. In one non-limiting embodiment, aryl groups are pendant. Anexample of a pendant ring is a phenyl group substituted with a phenylgroup. In an alternative embodiment, the aryl group is optionallysubstituted as described above. In certain embodiments, the aryl groupis an unsubstituted C₆₋₁₄ aryl. In certain embodiments, the aryl groupis a substituted C₆₋₁₄ aryl. An aryl group may be optionally substitutedwith one or more functional groups that include but are not limited to,halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, andheterocyclo.

The term “heterocyclyl” (or “heterocyclo”) includes saturated, andpartially saturated heteroatom-containing ring radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen.Heterocyclic rings comprise monocyclic 3-8 membered rings, as well as5-16 membered bicyclic ring systems (which can include bridged fused andspiro-fused bicyclic ring systems). It does not include rings containing—O—O—.—O—S— or —S—S— portions. Said “heterocyclyl” group may beoptionally substituted, for example, with 1, 2, 3, 4 or moresubstituents that include but are not limited to, hydroxyl, Boc, halo,haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino. Examples ofsaturated heterocyclo groups include saturated 3- to 6-memberedheteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g.pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl];saturated 3 to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partiallysaturated heterocyclyl radicals include but are not limited to,dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.Examples of partially saturated and saturated heterocyclo groups includebut are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl.

Heterocyclo groups also include radicals where heterocyclic radicals arefused/condensed with aryl or heteroaryl radicals: such as unsaturatedcondensed heterocyclic group containing 1 to 5 nitrogen atoms, forexample, indoline, isoindoline, unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturatedcondensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, and saturated, partially unsaturated and unsaturatedcondensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms.

The term “heteroaryl” denotes aryl ring systems that contain one or moreheteroatoms selected from O, N and S, wherein the ring nitrogen andsulfur atom(s) are optionally oxidized, and nitrogen atom(s) areoptionally quarternized. Examples include but are not limited to,unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, IH-1,2,3-triazolyl, 2H-1,2,3-triazolyl];unsaturated 5- to 6-membered heteromonocyclic groups containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5to 6-membered heteromonocyclic groups containing a sulfur atom, forexample, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-memberedheteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “optionally substituted” denotes the substitution of a groupherein by a moiety including, but not limited to, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ cycloalkenyl, C₁-C₁₂heterocycloalkyl, C₃-C₁₂ heterocycloalkenyl, C₁-C₁₀ alkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, amino, C₁-C₁₀ alkylamino, C₁-C₁₀dialkylamino, arylamino, diarylamino, C₁-C₁₀ alkylsulfonamino,arylsulfonamino, C₁-C₁₀ alkylimino, arylimino, C₁-C₁₀ alkylsulfonimino,arylsulfonimino, hydroxyl, halo, thio, C₁-C₁₀ alkylthio, arylthio,C₁-C₁₀ alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl,amidino, guanidine, ureido, cyano, nitro, azido, acyl, thioacyl,acyloxy, carboxyl, and carboxylic ester.

In one alternative embodiment any suitable group may be present on a“substituted” or “optionally substituted” position if indicated thatforms a stable molecule and meets the desired purpose of the inventionand includes, but is not limited to, e.g., halogen (which canindependently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido;alkanoyl (such as a C₂-C₆ alkanoyl group); carboxamide; alkyl,cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkylincluding those having one or more thioether linkages; alkylsulfinyl;alkylsulfonyl groups including those having one or more sulfonyllinkages; aminoalkyl groups including groups having more than one Natoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ringeither substituted or unsubstituted); arylalkyl having for example, 1 to3 separate or fused rings and from 6 to about 14 or 18 ring carbonatoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, forexample, having 1 to 3 separate or fused rings with benzyloxy being anexemplary arylalkoxy group; or a saturated or partially unsaturatedheterocycle having 1 to 3 separate or fused rings with one or more N, Oor S atoms, or a heteroaryl having 1 to 3 separate or fused rings withone or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl,quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl,thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl,indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, andpyrrolidinyl. Such groups may be further substituted, e.g. with hydroxy,alkyl, alkoxy, halogen and amino. In certain embodiments “optionallysubstituted” includes one or more substituents independently selectedfrom halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH₂, alkylincluding C₁-C₆alkyl, alkenyl including C₂-C₆alkenyl, alkynyl includingC₂-C₆alkynyl, —C₁-C₆alkoxy, alkanoyl including C₂-C₆alkanoyl,C₁-C₆alkylester, (mono- and di-C₁-C₆alkylamino)C₀-C₂alkyl, haloalkylincluding C₁-C₆haloalkyl, hydoxyC₁-C₆alkyl, ester, carbamate, urea,sulfonamide, —C₁-C₆alkyl(heterocyclo), C₁-C₆alkyl(heteroaryl),—C₁-C₆alkyl(C₃-C₇cycloalkyl), O—C₁-C₆alkyl(C₃-C₇cycloalkyl), B(OH)₂,phosphate, phosphonate and haloalkoxy including C₁-C₆haloalkoxy.

“Aliphatic” refers to a saturated or unsaturated, straight, branched, orcyclic hydrocarbon. “Aliphatic” is intended herein to include, but isnot limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, andcycloalkynyl moieties, and thus incorporates each of these definitions.In one embodiment, “aliphatic” is used to indicate those aliphaticgroups having 1-20 carbon atoms. The aliphatic chain can be, forexample, mono-unsaturated, di-unsaturated, tri-unsaturated, orpolyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in acis or trans configuration. In one embodiment, the aliphatic groupcontains from 1 to about 12 carbon atoms, more generally from 1 to about6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment, thealiphatic group contains from 1 to about 8 carbon atoms. In certainembodiments, the aliphatic group is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅ or C₁-C₆.The specified ranges as used herein indicate an aliphatic group havingeach member of the range described as an independent species. Forexample, the term C₁-C₆ aliphatic as used herein indicates a straight orbranched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or6 carbon atoms and is intended to mean that each of these is describedas an independent species. For example, the term C₁-C₄ aliphatic as usedherein indicates a straight or branched alkyl, alkenyl, or alkynyl grouphaving from 1, 2, 3, or 4 carbon atoms and is intended to mean that eachof these is described as an independent species. In one embodiment, thealiphatic group is substituted with one or more functional groups thatresults in the formation of a stable moiety.

The term “heteroaliphatic” refers to an aliphatic moiety that containsat least one heteroatom in the chain, for example, an amine, carbonyl,carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus,silicon, or boron atoms in place of a carbon atom. In one embodiment,the only heteroatom is nitrogen. In one embodiment, the only heteroatomis oxygen. In one embodiment, the only heteroatom is sulfur.“Heteroaliphatic” is intended herein to include, but is not limited to,heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment,“heteroaliphatic” is used to indicate a heteroaliphatic group (cyclic,acyclic, substituted, unsubstituted, branched or unbranched) having 1-20carbon atoms. In one embodiment, the heteroaliphatic group is optionallysubstituted in a manner that results in the formation of a stablemoiety. Nonlimiting examples of heteroaliphatic moieties arepolyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide,polyglycolide, thioether, ether, alkyl-heterocycle-alkyl,—O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, implants, particles, spheres, creams,ointments, suppositories, inhalable forms, transdermal forms, buccal,sublingual, topical, gel, mucosal, and the like. A “dosage form” canalso include an implant, for example an optical implant.

An “effective amount” as used herein, means an amount which provides atherapeutic or prophylactic benefit.

As used herein “endogenous” refers to any material from or producedinside an organism, cell, tissue or system.

As used herein, the term “exogenous” refers to any material introducedfrom or produced outside an organism, cell, tissue or system.

By the term “modulating,” as used herein, is meant mediating adetectable increase or decrease in the level of a response in a subjectcompared with the level of a response in the subject in the absence of atreatment or compound, and/or compared with the level of a response inan otherwise identical but untreated subject. The term encompassesperturbing and/or affecting a native signal or response therebymediating a beneficial therapeutic response in a subject, preferably, ahuman.

“Parenteral” administration of an immunogenic composition includes,e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), orintrasternal injection, or infusion techniques.

As used herein, the terms “peptide,” “polypeptide,” and “protein” areused interchangeably, and refer to a compound comprised of amino acidresidues covalently linked by peptide bonds. A protein or peptide mustcontain at least two amino acids, and no limitation is placed on themaximum number of amino acids that can comprise a protein's or peptide'ssequence. Polypeptides include any peptide or protein comprising two ormore amino acids joined to each other by peptide bonds. As used herein,the term refers to both short chains, which also commonly are referredto in the art as peptides, oligopeptides and oligomers, for example, andto longer chains, which generally are referred to in the art asproteins, of which there are many types. “Polypeptides” include, forexample, biologically active fragments, substantially homologouspolypeptides, oligopeptides, homodimers, heterodimers, variants ofpolypeptides, modified polypeptides, derivatives, analogs, fusionproteins, among others. The polypeptides include natural peptides,recombinant peptides, synthetic peptides, or a combination thereof.

To “treat” a disease as the term is used herein, means to reduce thefrequency or severity of at least one sign or symptom of a disease ordisorder experienced by a subject.

Ranges: throughout this disclosure, various aspects of the invention canbe presented in a range format. It should be understood that thedescription in range format is merely for convenience and should not beconstrued as a limitation on the scope of the invention. The descriptionof a range should be considered to have specifically disclosed all thepossible subranges as well as individual numerical values within thatrange. For example, description of a range such as from 1 to 6 should beconsidered to have specifically disclosed subranges such as from 1 to 3,from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., aswell as individual numbers within that range, for example, 1, 2, 2.7, 3,4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

As used herein, “pharmaceutical compositions” are compositionscomprising at least one active agent, and at least one other substance,such as a carrier. “Pharmaceutical combinations” are combinations of atleast two active agents which may be combined in a single dosage form orprovided together in separate dosage forms with instructions that theactive agents are to be used together to treat any disorder describedherein.

As used herein, “pharmaceutically acceptable salt” is a derivative ofthe disclosed compound in which the parent compound is modified bymaking inorganic and organic, non-toxic, acid or base addition saltsthereof. The salts of the present compounds can be synthesized from aparent compound that contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting freeacid forms of these compounds with a stoichiometric amount of theappropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate, or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, non-aqueous media like ether,ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, wherepracticable. Salts of the present compounds further include solvates ofthe compounds and of the compound salts.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like, or using a differentacid that produces the same counterion. Lists of additional suitablesalts may be found, e.g., in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

The term “carrier” applied to pharmaceutical compositions/combinationsof the invention refers to a diluent, excipient, or vehicle with whichan active compound is provided.

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition/combination that isgenerally safe, non-toxic and neither biologically nor otherwiseinappropriate for administration to a host, typically a human. In oneembodiment, an excipient is used that is acceptable for veterinary use.

A “patient” or “host” or “subject” is a human or non-human animal inneed of treatment or prevention of any of the disorders as specificallydescribed herein, for example that is modulated by a natural (wild-type)or modified (non-wild type) protein that can be degraded according tothe present invention, resulting in a therapeutic effect. Typically, thehost is a human. A “host” may alternatively refer to for example, amammal, primate (e.g., human), cow, sheep, goat, horse, dog, cat,rabbit, rat, mice, fish, bird and the like.

A “therapeutically effective amount” of a pharmaceuticalcomposition/combination of this invention means an amount effective,when administered to a host, to provide a therapeutic benefit such as anamelioration of symptoms or reduction or diminution of the diseaseitself.

II. Compounds Formula I and Formula II

In one aspect of the present invention a Degronimer of Formula I orFormula II is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition;wherein:

the R moieties are as described above;

Linker is a chemical group that attaches the Degron to a TargetingLigand;

Targeting Ligand is a small molecule that binds to a Target Protein, andwherein the Target Protein is a mediator of disease in a host;

In an additional embodiment, R⁶ is selected from:

In an additional embodiment, R⁶ is selected from

In an additional embodiment, R⁶ is selected from

For example formula:

includes compounds of structure

as if each was specifically described.

The Degronimer (Degron, Linker and Targeting Ligand), which includes anyof the “R” groups defined herein, may be optionally substituted asdescribed below in Section I. Definitions, if desired to achieve thetarget effect, results in a stable R moiety and final compound thatmakes chemical sense to the routineer, and if a final compound fortherapy, is pharmaceutically acceptable. Also, all R groups, with orwithout optional substituents, should be interpreted in a manner thatdoes not include redundancy (i.e., as known in the art, alkylsubstituted with alkyl is redundant; however for examples, alkoxysubstituted with alkoxy is not redundant). Using this disclosure andteaching, one of ordinary skill in the art will be able to produce theDegronimers of the present invention, and can avoid those moieties thatare not stable or are too reactive under the appropriate conditions.

Non-limiting examples of R⁶ include:

Additional non-limiting examples of R⁶ include:

Non-limiting examples of compounds of Formula I include:

Additional non-limiting examples of compounds of Formula I include:

Non-limiting examples of compounds of Formula II include:

wherein:

R¹⁷ is selected from:

Non-limiting examples of compounds of Formula VII include:

Formula III and Formula IV

In one aspect of the present invention a compound of Formula III orFormula IV is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition;wherein:

W¹ is CR¹R², C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

W² is CR³R⁴, C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

in a typical embodiment W¹ is C═O;

in another typical embodiment W² is C═O;

X is independently selected from NH, NR¹², CH₂, CHR¹², C(R¹²)₂, O, or S;

n is 0, 1, 2, or 3;

is a single or double bond;

R¹⁶ is selected from:

In an additional embodiment, R¹⁶ is selected from:

In an additional embodiment, R¹⁶ is selected from:

In an additional embodiment, R¹⁶ is selected from

Y is independently selected from N, CH, or CR¹¹, wherein 0, 1, or 2instances of Y are selected to be N;

or 3 instances of Y are selected to be N;

Z is NH, O, S, or NR¹²;

Z² is NH or NR¹²;

R¹, R², R³, R⁴, R⁷, R, and R¹⁵ are independently selected from hydrogen,alkyl, hydroxyl, alkoxy, amine, —NHalkyl, and —Nalkyl₂ each of which isoptionally substituted as described in the Definition Section, ifdesired to achieve the target effect, results in a stable compound thatmakes chemical sense to the routineer, and the group is not redundant(i.e., as known in the art, alkyl substituted with alkyl is redundant;however for examples, alkoxy substituted with alkoxy is not redundant);

or R¹ and R² together with the carbon to which they are attached form a3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-memberedspiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R³ and R⁴ together with the carbon to which they are attached form a3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-memberedspiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R⁷ and R⁸ together with the carbon to which they are attached form a3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-memberedspiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R¹ and R³ form a 1 or 2 carbon bridged ring;

or R¹ and R⁷ form a 1 or 2 carbon bridged ring;

or R³ and R⁷ form a 1 or 2 carbon bridged ring;

or R¹⁵ and R¹ form a 3, 4, 5, or 6 carbon fused ring;

or R¹⁵ and R⁷ form a 3, 4, 5, or 6 carbon fused ring;

or R¹⁵ and R³ form a 1 or 2 carbon bridged ring;

or R¹⁵ and R⁵ form a 3, 4, 5, or 6 carbon fused ring wherein R⁵ is onthe carbon alpha to R¹⁵ or a 1, 2, 3, or 4 carbon bridged ring whereinR⁵ is not on the carbon alpha to R¹⁵;

R⁵ is selected at each instance from: alkyl, alkene, alkyne, halogen,hydroxyl, alkoxy, azide, amino, —NHalkyl, —N(alkyl)₂, —NHSO₂alkyl,—N(alkyl)SO₂alkyl, —NHSO₂aryl, —N(alkyl)SO₂aryl, —NHSO₂alkenyl,—N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl, and haloalkyl,each of which is optionally substituted as described in the DefinitionSection, if desired to achieve the target effect, results in a stablecompound that makes chemical sense to the routineer, and the group isnot redundant (i.e., as known in the art, alkyl substituted with alkylis redundant; however for examples, alkoxy substituted with alkoxy isnot redundant);

or two R⁵ substituents together with the carbon atom(s) to which theyare bound can form a 3, 4, 5 or 6 membered ring;

R¹¹ is selected at each instance from: hydrogen, alkyl, alkenyl,alkynyl, halogen, hydroxyl, alkoxy, aryl, heteroaryl, alkylamino,alkylhydroxyl, —NHalkyl, —Nalkyl₂, amino, cyano, nitro, nitroso,sulfone, sulfoxide, thioalkyl, thiol and haloalkyl, each of which isoptionally substituted as described in the Definition Section, ifdesired to achieve the target effect, results in a stable compound thatmakes chemical sense to the routineer, and the group is not redundant(i.e., as known in the art, alkyl substituted with alkyl is redundant;however for examples, alkoxy substituted with alkoxy is not redundant);

R¹² is selected at each instance from: alkyl, —C(O)H, —C(O)OH,—C(O)alkyl, —C(O)Oalkyl, alkene, and alkyne;

R¹³ and R¹⁴ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, alkoxy, haloalkoxy, hydroxy, amino, —NHalkyl, and —N(alkyl)₂;

or R¹³ and R¹⁴ together with the carbon atom to which they are attached,form C(O), C(S), C═CH2, a 3-, 4-, 5-, or 6-membered spirocarbocycle, ora 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatomsselected from N and O.

Non-limiting examples of compounds of Formula III include:

Formula V-A

In one aspect of the present invention a compound of Formula V isprovided, wherein the compound of Formula V-A is selected from:

Formula V and Formula VI

In one aspect of the present invention a compound of Formula V orFormula VI is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug thereof, optionally in a pharmaceutically acceptable carrier toform a composition;wherein:

Non-limiting examples of compounds of Formula V include:

Non-limiting examples of compounds of Formula VI include:

Linker

A Linker is included in the Degronimers of Formula I, II, V and VII.Linker is a bond or a chemically stable group that attaches a Degron toa Targeting Ligand.

Any of the Linkers described herein can be used in either direction,i.e., either the left end is linked to the Degron and the right end tothe Target Linker, or the left end is linked to the Target Linker andthe right end is linked to the Degron. According to the invention, anydesired linker can be used as long as the resulting compound has astable shelf life for at least 2 months, 3 months, 6 months or 1 year aspart of a pharmaceutically acceptable dosage form, and itself ispharmaceutically acceptable.

In a typical embodiment, the Linker has a chain of 2 to 14, 15, 16, 17,18 or 20 or more carbon atoms of which one or more carbons can bereplaced by a heteroatom such as O, N, S, or P. In certain embodimentsthe chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19 or 20 contiguous atoms in the chain. For example, the chain mayinclude 1 or more ethylene glycol units that can be contiguous,partially contiguous or non-contiguous (for example, 2, 3, 4, 5, 6, 7,8, 9, 10, 11 or 12 ethylene glycol units). In certain embodiments thechain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous chains which canhave branches which can be independently alkyl, heteroalkyl, aryl,heteroaryl, alkenyl, or alkynyl, aliphatic, heteroaliphatic, cycloalkylor heterocyclic substituents.

In other embodiments, the linker can include or be comprised of one ormore of ethylene glycol, propylene glycol, lactic acid and/or glycolicacid. In general, propylene glycol adds hydrophobicity, while propyleneglycol adds hydrophilicity. Lactic acid segments tend to have a longerhalf-life than glycolic acid segments. Block and random lacticacid-co-glycolic acid moieties, as well as ethylene glycol and propyleneglycol, are known in the art to be pharmaceutically acceptable and canbe modified or arranged to obtain the desired half-life andhydrophilicity. In certain aspects, these units can be flanked orinterspersed with other moieties, such as aliphatic, including alkyl,heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc., asdesired to achieve the appropriate drug properties.

In one embodiment, the Linker is a moiety selected from Formula LI,Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, andFormula LVII:

wherein:

X¹ and X² are independently selected from bond, NH, NR²⁵, CH₂, CHR²⁵,C(R²⁵)₂, O, and S;

R²⁰, R²¹, R²², R²³, and R²⁴ are independently selected from bond, alkyl,—C(O)— —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO₂—, —S(O)—,—C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—,—NH—, —N(alkyl)-, —CH(—O—R²⁶)—, —CH(—NHR²⁵)—, —CH(—NH₂)—, —CH(—NR²⁵ ₂)—,—C(—O—R²⁶)alkyl-, —C(—NHR²⁵)alkyl-, —C(—NH₂)alkyl-, —C(—NR²⁵ ₂)alkyl-,—C(R⁴R⁴)—, -alkyl(R²⁷)-alkyl(R²⁸)—, —C(R²⁷R²⁸)—, —P(OXOR²⁶)O—,—P(OXOR²⁶)—, —NHC(O)NH—, —N(R²⁵)C(O)N(R²⁵)—, —N(H)C(O)N(R²⁵)—,polyethylene glycol, poly(lactic-co-glycolic acid), alkene, haloalkyl,alkoxy, and alkyne;

or R²⁰, R²¹, R²², R²³, and R²⁴ can in addition to those above beindependently selected from heteroarylalkyl, aryl, arylalkyl,heterocycle, aliphatic, heteroaliphatic, heteroaryl, polypropyleneglycol, lactic acid, glycolic acid, carbocycle, or —O—(CH₂)₁₋₁₂—O—,—NH—(CH₂)₁₋₁₂—NH—, —NH—(CH₂)₁₋₁₂—O—, or —O—(CH₂)₁₋₁₂—NH—,—S—(CH₂)₁₋₁₂—O—, —O—(CH₂)₁₋₁₂—S—, —S—(CH₂)₁₋₁₂—S—, —S—(CH₂)₁₋₁₂—NH—,—NH—(CH₂)₁₋₁₂—S—, (and wherein the 1-12 can be independently 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11 or 12, and wherein one or more of the CH₂ or NHcan be modified by substitution of a H for a methyl, ethyl, cyclopropyl,F (if on carbon), etc, as described herein), and optionally, aheteroatom, heteroalkyl, aryl, heteroaryl or cycloaliphatic group isinterspersed in the chain). Certain nonlimiting examples include—O—CH(CH₃)—CH(CH₃)CH—O—, —O—CH₂—CH(CH₃)CH—O—, —O—CH(CH₃)—CH₂CH—O—, etc.

each of which R²⁰, R²¹, R²², R²³, and R²⁴ is optionally substituted withone or more substituents selected from R¹⁰¹ or alternatively asdescribed in Section 1. Definitions; and

R²⁵ is selected at each instance from: alkyl, —C(O)H, —C(O)OH,—C(O)alkyl, —C(O)Oalkyl, alkenyl, or alkynyl or alternatively can bealiphatic, heteroaliphatic, aryl, heteroaryl or heterocyclic;

R²⁶ is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, andalkyne; or in addition to these can also be selected from aryl,heteroaryl, heterocyclic, aliphatic and heteroaliphatic;

R²⁷ and R²⁸ are independently selected from hydrogen, alkyl, amine, ortogether with the carbon atom to which they are attached, form C(O),C(S), C═CH₂, a C₃-C₆ spirocarbocycle, or a 4-, 5-, or 6-memberedspiroheterocycle comprising 1 or 2 heteroatoms selected from N and O, orform a 1 or 2 carbon bridged ring;

R¹⁰¹ is independently selected at each occurrence from hydrogen, alkyl,alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl,heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy,heteroaryloxy, CN, —COOalkyl, COOH, NO₂, F, Cl, Br, I, CF₃, NH₂,NHalkyl, N(alkyl)₂, aliphatic, heteroaliphatic; and

R⁴ is independently selected from hydrogen, alkyl, hydroxyl, alkoxy,amine, —NHalkyl, and —Nalkyl₂ each of which is optionally substituted asdescribed in the Definition Section, if desired to achieve the targeteffect, results in a stable compound that makes chemical sense to theroutineer, and the group is not redundant (i.e., as known in the art,alkyl substituted with alkyl is redundant; however for examples, alkoxysubstituted with alkoxy is not redundant).

In an additional embodiment, the Linker is a moiety selected fromFormula LVIII, LIX, and LX:

wherein each variable is as it is defined in Formula LI. In alternativeembodiments of LVIII, LIX and LX, a carbocyclic ring is used in place ofthe heterocycle.

The following are non-limiting examples of Linkers that can be used inthis invention. Based on this elaboration, those of skill in the artwill understand how to use the full breadth of Linkers that willaccomplish the goal of the invention.

As certain non-limiting examples, Formula LI, Formula LII, Formula LIII,Formula LIV, Formula LV, Formula LVI, or Formula LVII include:

In an additional embodiment Linker is selected from:

In an additional embodiment Linker is selected from:

In one embodiment X¹ is attached to the Targeting Ligand. In anotherembodiment X² is attached to the Targeting Ligand.

Non-limiting examples of moieties of R², R²¹, R²², R²³, and R²⁴ include:

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, andR²⁴ include:

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, andR²⁴ include:

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, andR²⁴ include:

Additional non-limiting examples of moieties of R²⁰, R²¹, R²², R²³, andR²⁴ include:

In additional embodiments, the Linker group is an optionally substituted(poly)ethylene glycol having at least 1, at least 2, at least 3, atleast 4, at least 5, at least 6, at least 7, at least 8, at least 9, atleast 10, ethylene glycol units, or optionally substituted alkyl groupsinterspersed with optionally substituted, O, N, S, P or Si atoms. Incertain embodiments, the Linker is flanked, substituted, or interspersedwith an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. Incertain embodiments, the Linker may be asymmetric or symmetrical. Insome embodiments, the Linker is a substituted or unsubstitutedpolyethylene glycol group ranging in size from about 1 to about 12ethylene glycol units, between 1 and about 10 ethylene glycol units,about 2 about 6 ethylene glycol units, between about 2 and 5 ethyleneglycol units, between about 2 and 4 ethylene glycol units. In any of theembodiments of the compounds described herein, the Linker group may beany suitable moiety as described herein.

In additional embodiments, the Linker is selected from:

-   —NR⁶¹(CH₂)_(n1)-(lower alkyl)-, —NR⁶¹(CH₂)_(n1)-(lower alkoxyl)-,-   —NR⁶¹(CH₂)_(n1)-(lower alkoxyl)-OCH₂—, —NR⁶¹(CH₂)_(n1)-(lower    alkoxyl)-(lower alkyl)-OCH₂—,-   —NR⁶¹(CH₂)_(n1)-(cycloalkyl)-(lower alkyl)-OCH₂—,    —NR⁶¹(CH₂)_(n1)-(heterocycloalkyl)-,-   —NR⁶¹(CH₂CH₂O)_(n1)-(lower alkyl)-O—CH₂—,    —NR⁶¹(CH₂CH₂O)_(n1)-(heterocycloalkyl)-O—CH₂—,-   —NR⁶¹(CH₂CH₂O)_(n1)-Aryl-O—CH₂—,    —NR⁶¹(CH₂CH₂O)_(n1)-(heteroaryl)-O—CH₂—,-   —NR⁶¹(CH₂CH₂O)_(n1)-(cycloalkyl)-O-(heteroaryl)-O—CH₂—,-   —NR⁶¹(CH₂CH₂O)_(n1)-(cycloalkyl)-O-Aryl-O—CH₂—,-   —NR⁶¹(CH₂CH₂O)_(n1)-(lower alkyl)-NH-Aryl-O—CH₂—,-   —NR⁶¹(CH₂CH₂O)_(n1)-(lower alkyl)-O-Aryl-CH₂,-   —NR⁶¹(CH₂CH₂O)_(n1)-cycloalkyl-O-Aryl-,    —NR⁶¹(CH₂CH₂O)_(n1)-cycloalkyl-O-heteroaryl-,-   —NR⁶¹(CH₂CH₂)_(n1)-(cycloalkyl)-O-(heterocycle)-CH₂,-   —NR⁶(CH₂CH₂)_(n1)-(heterocycle)-(heterocycle)-CH₂, and    —NR⁶¹-(heterocycle)-CH₂;    wherein n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or; and    R⁶¹ is H, methyl, or ethyl.

In additional embodiments, the Linker is selected from:

-   —N(R⁶¹)—(CH₂)_(m1)—O(CH)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OCH₂—,-   —O—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OCH₂—,-   —O—(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—O—;-   —N(R⁶¹)—(CH₂)_(m1)—O(CH)_(n2)—O(CH)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—O—;-   —(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—O—;-   —(CH₂)_(m1)—O(CH₂)_(n2)—O(CH₂)_(o1)—O(CH₂)_(p1)—O(CH₂)_(q1)—O(CH₂)_(r1)—OCH₂—;-   —O(CH₂)_(m1)O(CH₂)_(n2)O(CH₂)_(p1)O(CH₂)_(q1)OCH₂—;-   —O(CH₂)_(m1)O(CH₂)_(n2)O(CH₂)_(p1)O(CH₂)_(q1)OCH₂—; wherein    m1, n2, o1, p1, q1, and r1 are independently 1, 2, 3, 4, or 5; and    R⁶¹ is H, methyl, or ethyl.

In additional embodiments, the Linker is selected from:

m1, n2, o1, p1, q2, and r1 are independently 1, 2, 3, 4, or 5.

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

wherein R⁷¹ is —O—, —NH, Nalkyl, heteroaliphatic, aliphatic, or —NMe.

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

In additional embodiments, the Linker is selected from:

In certain additional embodiments, the Linker is selected from:

In certain embodiments the Linker is selected from:

In the above structures

represents

In certain embodiments, Linker can be a 4-24 carbon atom linear chains,wherein one or more the carbon atoms in the linear chain can be replacedor substituted with oxygen, nitrogen, amide, fluorinated carbon, etc.,such as the following:

In certain embodiments, Linker can be a nonlinear chain, and can be, orinclude, aliphatic or aromatic or heteroaromatic cyclic moieties.

In certain embodiments, the Linker may include contiguous, partiallycontiguous or non-contiguous ethylene glycol unit groups ranging in sizefrom about 1 to about 12 ethylene glycol units, between 1 and about 10ethylene glycol units, about 2 about 6 ethylene glycol units, betweenabout 2 and 5 ethylene glycol units, between about 2 and 4 ethyleneglycol units, for example, 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12ethylene glycol units.

In certain embodiments, the Linker may have 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 fluorine substituents. In another embodimentthe Linker is perfluorinated. In yet another embodiment the Linker is apartially or fully fluorinated poly ether. Nonlimiting examples offluorinated Linkers include:

In certain embodiments, where the Target Ligand binds more than oneprotein (i.e., is not completely selective), selectivity may be enhancedby varying Linker length where the ligand binds some of its targets indifferent binding pockets, e.g., deeper or shallower binding pocketsthan others. Therefore, the length can be adjusted as desired.

In certain embodiments, the present application provides Degron-Linker(DL) having the following structure:

In an alternative embodiment, the present application providesDegron-Linker (DL) having the following structure:

wherein each of the variables is as described above in Formula I andFormula LI; and

a Targeting Ligand is covalently bonded to the DL through the

next to X².

Target Proteins

Degradation of cellular proteins is required for cell homeostasis andnormal cell function, such as proliferation, differentiation and celldeath. When this system becomes dysfunctional or does not identify andabate abnormal protein behavior in vivo, a disease state can arise in ahost, such as a human. A large range of proteins can cause, modulate oramplify diseases in vivo, as well known to those skilled in the art,published in literature and patent filings as well as presented inscientific presentations.

Therefore, in one embodiment, a selected Degronimer of the presentinvention can be administered in vivo in an effective amount to a hostin need thereof to degrade a selected protein that mediates a disorderto be treated. The selected Target Protein may modulate a disorder in ahuman via a mechanism of action such as modification of a biologicalpathway, pathogenic signaling or modulation of a signal cascade orcellular entry. In one embodiment, the Target Protein is a protein thatis not druggable in the classic sense in that it does not have a bindingpocket or an active site that can be inhibited or otherwise bound, andcannot be easily allosterically controlled. In another embodiment, theTarget Protein is a protein that is druggable in the classic sense, yetfor therapeutic purposes, degradation of the protein is preferred toinhibition.

The Target Protein is recruited with a Targeting Ligand for the TargetProtein. Typically the Targeting Ligand binds the Target Protein in anon-covalent fashion. In an alternative embodiment, the Target Proteinis covalently bound to the Degron in a manner that can be irreversibleor reversible.

In one embodiment, the selected Target Protein is expressed from a genethat has undergone an amplification, translocation, deletion, orinversion event which causes or is caused by a medical disorder. Incertain aspects, the selected Target Protein has beenpost-translationally modified by one, or a combination, ofphosphorylation, acetylation, acylation including propionylation andcrotylation, N-linked glycosylation, amidation, hydroxylation,methylation and poly-methylation, O-linked glycosylation,pyrogultamoylation, myristoylation, farnesylation, geranylgeranylation,ubiquitination, sumoylation, or sulfation which causes or is caused by amedical disorder.

As contemplated herein, the present invention includes an Degronimerwith a Targeting Ligand that binds to a Target Protein of interest. TheTarget Protein is any amino acid sequence to which an Degronimer can bebound which by degradation thereof, causes a beneficial therapeuticeffect in vivo. In one embodiment, the Target Protein is anon-endogenous peptide such as that from a pathogen or toxin. In anotherembodiment, the Target Protein can be an endogenous protein thatmediates a disorder. The endogenous protein can be either the normalform of the protein or an aberrant form. For example, the Target Proteincan be a mutant protein found in cancer cells, or a protein, forexample, where a partial, or full, gain-of-function or loss-of-functionis encoded by nucleotide polymorphisms. In some embodiments, theDegronimer targets the aberrant form of the protein and not the normalform of the protein. In another embodiment, the Target Protein canmediate an inflammatory disorder or an immune disorder, including anauto-immune disorder.

In one embodiment, the Target Protein is a non-endogenous protein from avirus, as non-limiting examples, HIV, HBV, HCV, RSV, HPV, CMV,flavivirus, pestivirus, coronavirus, noroviridae, etc. In oneembodiment, the Target Protein is a non-endogenous protein from abacteria, which may be for example, a gram positive bacteria, gramnegative bacteria or other, and can be a drug-resistant form ofbacteria. In one embodiment, the Target Protein is a non-endogenousprotein from a fungus. In one embodiment, the Target Protein is anon-endogenous protein from a prion. In one embodiment, the TargetProtein is a protein derived from a eukaryotic pathogen, for example aprotist, helminth, etc.

In one aspect, the Target Protein mediates chromatin structure andfunction. The Target Protein may mediate an epigenetic action such asDNA methylation or covalent modification of histones. An example ishistone deacetylase (HDAC 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11).Alternatively, the Target Protein may be a bromodomain, which arereaders of lysine acetylation (for example, BRD1, 2, 3, 4, 5, 6, 7, 8, 9and T. FIG. 9 is a dendogram of the proteins of the bromodomain family,which, for example, can act as Target Proteins according to the presentinvention.

Other nonlimiting examples of Target Proteins are a structural protein,receptor, enzyme, cell surface protein, a protein involved in apoptoticsignaling, aromatase, helicase, mediator of a metabolic process(anabolism or catabolism), antioxidant, protease, kinase,oxidoreductase, transferase, hydrolase, lyase, isomerase, ligase, enzymeregulator, signal transducer, structural molecule, binding activity(protein, lipid carbohydrate), cell motility protein, membrane fusionprotein, cell communication mediator, regulator of biological processes,behavioral protein, cell adhesion protein, protein involved in celldeath, protein involved in transport (including protein transporteractivity, nuclear transport, ion transporter, channel transporter,carrier activity, permease, secretase or secretion mediator, electrontransporter, chaperone regulator, nucleic acid binding, transcriptionregulator, extracellular organization and biogenesis regulator, andtranslation regulator).

In one embodiment, the Target Protein is a modulator of a signalingcascade related to a known disease state. In another embodiment, theTarget Protein mediates a disorder by a mechanism different frommodulating a signaling cascade. Any protein in a eukaryotic system or amicrobial system, including a virus, bacteria or fungus, as otherwisedescribed herein, are targets for proteasomal degradation using thepresent invention. The Target Protein may be a eukaryotic protein, andin some embodiments, a human protein.

In one embodiment, the Target Protein is RXR, DHFR, Hsp90, a kinase,HDM2, MDM2, BET bromodomain-containing protein, HDAC, IDH1, Mcl-1, humanlysine methyltransferase, a nuclear hormone receptor, aryl hydrocarbonreceptor (AHR), RAS, RAF, FLT, SMARC, KSR, NF2L, CTNB, CBLB, BCL.

In one embodiment, a bromodomain containing protein has histone acetyltransferase activity.

In one embodiment, the bromodomain containing protein is BRD2, BRD3,BRD4, BRDT or ASH1L.

In one embodiment, the bromodomain containing protein is a non-BETprotein.

In one embodiment, the non-BET protein is BRD7 or BRD9.

In one embodiment, the FLT is not FLT 3. In one embodiment, the RAS isnot RASK. In one embodiment, the RAF is not RAF1. In one embodiment, theSMARC is not SMARC2. In one embodiment, the KSR is not KSR1. In oneembodiment, the NF2L is not NF2L2. In one embodiment, the CTNB is notCTNB1. In one embodiment, the BCL is not BCL6.

In one embodiment, the Target Protein is selected from: EGFR, FLT3,RAF1, SMRCA2, KSR1, NF2L2, CTNB1, CBLB, BCL6, and RASK.

In another embodiment, the Target Protein is not selected from: EGFR,FLT3, RAF1, SMRCA2, KSR1, NF2L2, CTNB1, CBLB, BCL6, and RASK.

In one embodiment, the Targeting Ligand is an EGFR ligand, a FLT3ligand, a RAF1 ligand, a SMRCA2 ligand, a KSR1 ligand, a NF2L2 ligand, aCTNB1 ligand, a CBLB ligand, a BCL6 ligand, or a RASK ligand.

In one embodiment, the Targeting Ligand is not a EGFR ligand, a FLT3ligand, a RAF1 ligand, a SMRCA2 ligand, a KSR1 ligand, a NF2L2 ligand, aCTNB1 ligand, a CBLB ligand, a BCL6 ligand, or a RASK ligand.

The present invention may be used to treat a wide range of diseasestates and/or conditions, including any disease state and/or conditionin which a protein is dysregulated and where a patient would benefitfrom the degradation of proteins.

For example, a Target Protein can be selected that is a known target fora human therapeutic, and the therapeutic can be used as the TargetingLigand when incorporated into the Degronimer according to the presentinvention. These include proteins which may be used to restore functionin a polygenic disease, including for example B7.1 and B7, TINFR1m,TNFR2, NADPH oxidase, Bcl2/Bax and other partners in the apoptosispathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type,PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclaseinhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1,cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, e.g.,Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease,thymidylate synthase, purine nucleoside phosphorylase, GAPDHtrypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokinereceptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase,influenza, neuraminidase, hepatitis B reverse transcriptase, sodiumchannel, multi drug resistance (MDR), protein P-glycoprotein (and MRP),tyrosine kinases, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4integrin, selectins, CD40/CD40L, neurokinins and receptors, inosinemonophosphate dehydrogenase, p38 MAP Kinase, Ras/Raf/MER/ERK pathway,interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNAhelicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3Cprotease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus(CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases,vascular endothelial growth factor, oxytocin receptor, microsomaltransfer protein inhibitor, bile acid transport inhibitor, 5 alphareductase inhibitors, angiotensin 11, glycine receptor, noradrenalinereuptake receptor, endothelin receptors, neuropeptide Y and receptor,estrogen receptors, androgen receptors, adenosine receptors, adenosinekinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6,P2X1-7), farnesyltransferases, geranylgeranyl transferase, TrkA areceptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectinreceptor, integrin receptor, Her-2/neu, telomerase inhibition, cytosolicphospholipaseA2 and EGF receptor tyrosine kinase. Additional proteintargets include, for example, ecdysone 20-monooxygenase, ion channel ofthe GABA gated chloride channel, acetylcholinesterase, voltage-sensitivesodium channel protein, calcium release channel, and chloride channels.Still further Target Proteins include Acetyl-CoA carboxylase,adenylosuccinate synthetase, protoporphyrinogen oxidase, andenolpyruvylshikimate-phosphate synthase.

In certain embodiments, the Target Protein is derived from a kinase towhich the Targeting Ligand is capable of binding or binds including, butnot limited to, a tyrosine kinase (e.g., AATK, ABL, ABL2, ALK, AXL, BLK,BMX, BTK, CSF1R, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4,EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6,ERBB2, ERBB3, ERBB4, FER, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1,FLT3, FLT4, FRK, FYN, GSG2, HCK, IGF1R, ILK, INSR, INSRR, IRAK4, ITK,JAK1, JAK2, JAK3, KDR, KIT, KSR1, LCK, LMTK2, LMTK3, LTK, LYN, MATK,MERTK, MET, MLTK, MST1R, MUSK, NPR1, NTRK1, NTRK2, NTRK3, PDGFRA,PDGFRB, PLK4, PTK2, PTK2B, PTK6, PTK7, RET, ROR1, ROR2, ROS1, RYK,SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TIE1, TNK1, TNK2,TNNI3K, TXK, TYK2, TYRO3, YES1, or ZAP70).

In certain embodiments, the Target Protein is derived from a kinase towhich the Targeting Ligand is capable of binding or binds including, butnot limited to, a serine/threonine kinase (e.g., casein kinase 2,protein kinase A, protein kinase B, protein kinase C, Raf kinases, CaMkinases, AKT1, AKT2, AKT3, ALK, ALK2, ALK3, ALK4, Aurora A, Aurora B,Aurora C, CHK1, CHK2, CLK1, CLK2, CLK3, DAPK1, DAPK2, DAPK3, DMPK, ERK1,ERK2, ERK5, GCK, GSK3, HIPK, KHS1, LKB1, LOK, MAPKAPK2, MAPKAPK, MNK1,MSSK1, MST1, MST2, MST4, NDR, NEK2, NEK3, NEK6, NEK7, NEK9, NEK 1, PAK1,PAK2, PAK3, PAK4, PAK5, PAK6, PIM1, PIM2, PLK1, RIP2, RIP5, RSK1, RSK2,SGK2, SGK3, SIK1, STK33, TAO1, TAO2, TGF-beta, TLK2, TSSK1, TSSK2, ULK,or ULK2).

In certain embodiments, the Target Protein is derived from a kinase towhich the Targeting Ligand is capable of binding or binds including, butnot limited to a cyclin dependent kinase for example CDK1, CDK2, CDK3,CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13.

In certain embodiments, the Target Protein is derived from a kinase towhich the Targeting Ligand is capable of binding or binds including, butnot limited to a leucine-rich repeat kinase (e.g., LRRK2).

In certain embodiments, the Target Protein is derived from a kinase towhich the Targeting Ligand is capable of binding or binds including, butnot limited to a lipid kinase (e.g., PIK3CA, PIK3CB) or a sphingosinekinase (e.g. S1P).

In certain embodiments, the Target Protein is derived from a BETbromodomain-containing protein to which the Targeting Ligand is capableof binding or binds including, but not limited to, ASH1L, ATAD2, BAZ1A,BAZ1B, BAZ2A, BAZ2B, BRD1, BRD2, BRD3, BRD4, BRD5, BRD6, BRD7, BRD8,BRD9, BRD10, BRDT, BRPF1, BRPF3, BRWD3, CECR2, CREBBP, EP300, FALZ,GCN5L2, KIAA1240, LOC93349, MLL, PB1, PCAF, PHIP, PRKCBP1, SMARCA2,SMARCA4, SP100, SP110, SP140, TAF1, TAF1L, TIF1a, TRIM28, TRIM33,TRIM66, WDR9, ZMYND11, and MLL4. In certain embodiments, a BETbromodomain-containing protein is BRD4.

In certain embodiments, the Target Protein is derived from a nuclearprotein to which the Targeting Ligand is capable of binding or bindsincluding, but not limited to, BRD2, BRD3, BRD4, AntennapediaHomeodomain Protein, BRCA1, BRCA2, CCAAT-Enhanced-Binding Proteins,histones, Polycomb-group proteins, High Mobility Group Proteins,Telomere Binding Proteins, FANCA, FANCD2, FANCE, FANCF, hepatocytenuclear factors, Mad2, NF-kappa B, Nuclear Receptor Coactivators,CREB-binding protein, p55, p107, p130, Rb proteins, p53, c-fos, c-jun,c-mdm2, c-myc, and c-rel.

In one embodiment, the Target Protein is a protein, or a precursor,variant (e.g., a splice variant), mutant (e.g., substitution, deletion,duplication, insertion, insertion/deletion, extension, etc.), homolog,chimeric. polymorph, isoform, modification (e.g., post-translationallymodified through glycosylation, phosphorylation, proteolysis, etc.), orrecombinant thereof.

In certain embodiments, the Target Protein is a member of the Retinoid XReceptor (RXR) family and the disorder treated is a neuropsychiatric orneurodegenerative disorder. In certain embodiments, the Target Proteinis a member of the Retinoid X Receptor (RXR) family and the disordertreated is schizophrenia.

In certain embodiments, the Target Protein is dihydrofolate reductase(DHFR) and the disorder treated is cancer. In certain embodiments, theTarget Protein is dihydrofolate reductase (DHFR) and the disordertreated is microbial.

In certain embodiments, the Target Protein is dihydrofolate reductasefrom bacillus anthracis (BaDHFR) and the disorder treated is anthrax.

In certain embodiments, the Target Protein is Heat Shock Protein 90(HSP90) and the disorder treated is cancer.

In certain embodiments, the Target Protein is a kinase or phosphataseand the disorder treated is cancer.

In certain embodiments, the Target Protein is HDM2 and or MDM2 and thedisorder treated is cancer.

In certain embodiments, the Target Protein is a BET bromodomaincontaining protein and the disorder treated is cancer.

In certain embodiments, the Target Protein is a lysine methyltransferaseand the disorder treated is cancer.

In certain embodiments, the Target Protein belongs to the RAF family andthe disorder treated is cancer.

In certain embodiments, the Target Protein belongs to the FKBP familyand the disorder treated is an autoimmune disorder. In certainembodiments, the Target Protein belongs to the FKBP family and thedisorder treated is organ rejection. In certain embodiments, the TargetProtein belongs to the FKBP family and the compound is givenprophylactically to prevent organ failure.

In certain embodiments, the Target Protein is an androgen receptor andthe disorder treated is cancer.

In certain embodiments, the Target Protein is an estrogen receptor andthe disorder treated is cancer.

In certain embodiments, the Target Protein is a viral protein and thedisorder treated is a viral infection. In certain embodiments, theTarget Protein is a viral protein and the disorder treated is HIV, HPV,or HCV.

In certain embodiments, the Target Protein is an AP-1 or AP-2transcription factor and the disorder treated is cancer.

In certain embodiments, the Target Protein is a HIV protease and thedisorder treated is a HIV infection. In certain embodiments, the TargetProtein is a HIV integrase and the disorder treated is a HIV infection.In certain embodiments, the Target Protein is a HCV protease and thedisorder treated is a HCV infection. In certain embodiments, thetreatment is prophylactic and the Target Protein is a viral protein.

In certain embodiments, the Target Protein is a member of the histonedeacetylase (HDAC) family and the disorder is a neurodegenerativedisorder. In certain embodiments, the Target Protein is a member of thehistone deacetylase (HDAC) family and the disorder is Huntingon's,Parkinson's, Kennedy disease, amyotropic lateral sclerosis,Rubinstein-Taybi syndrome, or stroke.

In certain embodiments, the Target Protein as referred to herein isnamed by the gene that expresses it. The person skilled in the art willrecognize that when a gene is referred to as a Target Protein, theprotein encoded by the gene is the Target Protein. For example, ligandsfor the protein SMCA2 which is encoded by SMRCA2 are referred to asSMRCA2 Targeting Ligands.

Targeting Ligands

In certain aspects, the Targeting Ligand is a ligand which covalently ornon-covalently binds to a Target Protein which has been selected forproteasomal degradation by the selected Degronimer. FIGS. 1A-8PPPPPdescribe targeting ligands for a number of proteins wherein R is thepoint of attachment for the linker. While specific targeting ligands areexemplified in the figures, additional ligands and examples can be foundin the references cited in the brief description of figures or aregenerally known in the art.

In one embodiment, the Targeting Ligand binds to an endogenous proteinwhich has been selected for degradation as a means to achieve atherapeutic effect on the host. Illustrative Targeting Ligands include:RXR ligands, DHFR ligands, Hsp90 inhibitors, kinase inhibitors, HDM2 andMDM2 inhibitors, compounds targeting Human BET bromodomain-containingproteins, HDAC inhibitors, ligands of MerTK, ligands of IDH1, ligands ofMcl-1, ligands of SMRCA2, ligands of EGFR, ligands of RAF, ligands ofcRAF, human lysine methyltransferase inhibitors, angiogenesisinhibitors, nuclear hormone receptor compounds, immunosuppressivecompounds, and compounds targeting the aryl hydrocarbon receptor (AHR),among numerous others. Targeting Ligands also considered to includetheir pharmaceutically acceptable salts, prodrugs and isotopicderivatives.

In certain aspects, the Targeting Ligand binds to a dehalogenase enzymein a patient or subject or in a diagnostic assay and is a haloalkane(preferably a C₁-C₁₀alkyl group which is substituted with at least onehalo group, preferably a halo group at the distal end of the alkyl group(i.e., away from the Linker). In still other embodiments, the TargetingLigand is a haloalkyl group, wherein said alkyl group generally rangesin size from about 1 or 2 carbons to about 12 carbons in length, oftenabout 2 to 10 carbons in length, often about 3 carbons to about 8carbons in length, more often about 4 carbons to about 6 carbons inlength. The haloalkyl groups are generally linear alkyl groups (althoughbranched-chain alkyl groups may also be used) and are end-capped with atleast one halogen group, preferably a single halogen group, often asingle chloride group. Haloalkyl PT, groups for use in the presentinvention are preferably represented by the chemicalstructure—(CH₂)_(v)-Halo where v is any integer from 2 to about 12,often about 3 to about 8, more often about 4 to about 6. Halo may be anyhalogen, but is preferably Cl or Br, more often Cl.

In certain embodiments, the Targeting Ligand is a retinoid X receptor(RXR) agonist or antagonist. Non-limiting examples include retinol,retinoic acid, bexarotene, docosahexenoic acid, compounds disclosed inWO 9929324, the publication by Canan Koch et al. (J. Med. Chem. 1996,39, 3229-3234) titled “Identification of the First Retinoid X ReceptorHomodimer Antagonist”, WO 9712853, EP 0947496A1, WO 2016002968, andanalogs thereof.

In certain embodiments, the Targeting Ligand is a DHFR agonist orantagonist. Non-limiting examples include folic acid, methotrexate,8,10-dideazatetrahydrofolate compounds disclosed by Tian et al. (Chem.Biol. Drug Des. 2016, 87, 444-454) titled “Synthesis, Antifolate andAnticancer Activities of N5-Substituted 8,10-DideazatetrahydrofolateAnalogues”, compounds prepared by Kaur et al. (Biorg. Med. Chem. Lett.2016, 26, 1936-1940) titled “Rational Modification of the Lead Molecule:Enhancement in the Anticancer and Dihydrofolate Reductase InhibitoryActivity”, WO 2016022890, compounds disclosed by Zhang et al. (Int. J.Antimicrob. Agents 46, 174-182) titled “New Small-Molecule Inhibitors ofDihydrofolate Reductase Inhibit Streptococcus Mutans”, modifiedtrimethoprim analogs developed by Singh et al. (J. Med. Chem. 2012, 55,6381-6390) titled “Mechanism Inspired Development of Rationally DesignedDihydrofolate Reductase Inhibitors as Anticancer Agents”, WO20111153310,and analogs thereof.

In certain embodiments, the Targeting Ligand derived from estrogen, anestrogen analog, SERM (selective estrogen receptor modulator), a SERD(selective estrogen receptor degrader), a complete estrogen receptordegrader, or another form of partial or complete estrogen antagonist oragonist. Examples are the partial anti-estrogens raloxifene andtamoxifen and the complete antiestrogen fulvestrant. Non-limitingexamples of anti-estrogen compounds are provided in WO 2014/19176assigned to Astra Zeneca, WO2013/090921, WO 2014/203129, WO 2014/203132,and US2013/0178445 assigned to Olema Pharmaceuticals, and U.S. Pat. Nos.9,078,871, 8,853,423, and 8,703,810, as well as US 2015/0005286, WO2014/205136, and WO 2014/205138. Additional non-limiting examples ofanti-estrogen compounds include: SERMS such as anordrin, bazedoxifene,broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil,lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, andfulvestrant; aromatase inhibitors such as aminoglutethimide,testolactone, anastrozole, exemestane, fadrozole, formestane, andletrozole; and antigonadotropins such as leuprorelin, cetrorelix,allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinoneacetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate,nomegestrol acetate, norethisterone acetate, progesterone, andspironolactone. Other estrogenic ligands that can be used according tothe present invention are described in U.S. Pat. Nos. 4,418,068;5,478,847; 5,393,763; and 5,457,117, WO2011/156518, U.S. Pat. Nos.8,455,534 and 8,299,112, 9,078,871; 8,853,423; 8,703,810; US2015/0005286; and WO 2014/205138, US2016/0175289, US2015/0258080, WO2014/191726, WO 2012/084711; WO 2002/013802; WO 2002/004418; WO2002/003992; WO 2002/003991; WO 2002/003990; WO 2002/003989; WO2002/003988; WO 2002/003986; WO 2002/003977; WO 2002/003976; WO2002/003975; WO 2006/078834; U.S. Pat. No. 6,821,989; US 2002/0128276;U.S. Pat. No. 6,777,424; US 2002/0016340; U.S. Pat. Nos. 6,326,392;6,756,401; US 2002/0013327; U.S. Pat. Nos. 6,512,002; 6,632,834; US2001/0056099; U.S. Pat. Nos. 6,583,170; 6,479,535; WO 1999/024027; U.S.Pat. No. 6,005,102; EP 0802184; U.S. Pat. Nos. 5,998,402; 5,780,497,5,880,137, WO 2012/048058 and WO 2007/087684.

In certain embodiments, the Targeting Ligand is a HSP90 inhibitoridentified in Vallee et al. (J. Med. Chem. 2011, 54, 7206-7219) titled“Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I:Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors ofthe Hsp90 Molecular Chaperone”, including YKB(N-[4-(3H-imidazo[4,5-C]Pyridin-2-yl)-9H-Fluoren-9-yl]-succinamide), aHSP90 inhibitors (modified) identified in Brough et al. (J. Med. Chem.2008, 51, 196-218) titled “4,5-Diarylisoxazole Hsp90 ChaperoneInhibitors: Potential Therapeutic Agents for the Treatment of Cancer”,including compound 2GJ(5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide),the HSP90 inhibitor geldanamycin((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1](derivatized)or any of its derivatives (e.g. 17-alkylamino-17-desmethoxygeldanamycin(“17-AAG”) or 17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin(“17-DMAG”)), or a HSP90 inhibitor (modified) identified in Wright etal. (Chem. Biol. 2004, 11, 775-785) titled “Structure-ActivityRelationships in Purine-Based Inhibitor Binding to Hsp90 Isoforms”,including the HSP90 inhibitor PU3. Other non-limiting examples of Hsp90Targeting Ligands include SNX5422 currently in phase I clinical trialsReddy et al. (Clin. Lymphoma Myeloma Leuk. 2013, 13, 385-391) titled“Phase I Trial of the Hsp90 Inhibitor Pf-04929113 (Snx5422) in AdultPatients with Recurrent, Refractory Hematologic Malignancies”, orNVP-AUY922 whose anti-cancer activity was assessed by Jensen et al.(Breast Cancer Research: BCR 2008, 10, R33-R33) titled “Nvp-Auy922: ASmall Molecule Hsp90 Inhibitor with Potent Antitumor Activity inPreclinical Breast Cancer Models”.

In certain embodiments, the Targeting Ligand is a kinase inhibitoridentified in Millan et al. (J. Med. Chem. 2011, 54, 7797-7814) titled“Design and Synthesis of Inhaled P38 Inhibitors for the Treatment ofChronic Obstructive Pulmonary Disease”, including the kinase inhibitorsY1W and Y1X, a kinase inhibitor identified in Schenkel et al. (J. Med.Chem. 2011, 54, 8440-8450) titled “Discovery of Potent and HighlySelective Thienopyridine Janus Kinase 2 Inhibitors”, including thecompounds 6TP and 0TP, a kinase inhibitor identified in van Eis et al.(Biorg. Med. Chem. Lett. 2011, 21, 7367-7372) titled “2,6-Naphthyridinesas Potent and Selective Inhibitors of the Novel Protein Kinase CIsozymes”, including the kinase inhibitors 07U and YCF identified inLountos et al. (J. Struct. Biol. 2011, 176, 292-301) titled “StructuralCharacterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2),a Drug Target for Cancer Therapy”, including the kinase inhibitors XK9and NXP, afatinib, fostamatinib, gefitinib, lenvatinib, vandetanib,Gleevec, pazopanib, AT-9283, TAE684, nilotanib, NVP-BSK805, crizotinib,JNJ FMS, foretinib, OSI-027, OSI-930, or OSI-906.

In certain embodiments, the Targeting Ligand is a HDM2/MDM2 inhibitoridentified in Vassilev et al. (Science 2004, 303, 844-848) titled “InVivo Activation of the P53 Pathway by Small-Molecule Antagonists ofMdm2”, and Schneekloth et al. (Bioorg. Med. Chem. Lett. 2008, 18,5904-5908) titled “Targeted Intracellular Protein Degradation Induced bya Small Molecule: En Route to Chemical Proteomics”, including thecompounds nutlin-3, nutlin-2, and nutlin-1.

In certain embodiments, the Targeting Ligand is a Human BET BromodomainTargeting Ligand identified in Filippakopoulos et al. (Nature 2010, 468,1067-1073) titled “Selective Inhibition of Bet Bromodomains” such as JQ1; a ligand identified in Nicodeme et al. (Nature 2010, 468, 1119-1123)titled “Suppression of Inflammation by a Synthetic Histone Mimic”; Chunget al. (J. Med. Chem. 2011, 54, 3827-3838) titled “Discovery andCharacterization of Small Molecule Inhibitors of the Bet FamilyBromodomains”; a compound disclosed in Hewings et al. (J. Med. Chem.2011, 54, 6761-6770) titled “3,5-Dimethylisoxazoles Act asAcetyl-Lysine-Mimetic Bromodomain Ligands”; a ligand identified inDawson et al. (Nature 2011, 478, 529-533) titled “Inhibition of BetRecruitment to Chromatin as an Effective Treatment for MLL-FusionLeukaemia”; or a ligand identified in the following patent applicationsUS 2015/0256700, US 2015/0148342, WO 2015/074064, WO 2015/067770, WO2015/022332, WO 2015/015318, and WO 2015/011084.

In certain embodiments, the Targeting Ligand is a HDAC Targeting Ligandidentified in Finnin et al. (Nature 1999, 401, 188-193) titled“Structures of a Histone Deacetylase Homologue Bound to the Tsa and SahaInhibitors”, or a ligand identified as Formula (I) in PCT WO0222577.

In certain embodiments, the Targeting Ligand is a Human LysineMethyltransferase ligand identified in Chang et al. (Nat Struct Mol Biol2009, 16, 312-317) titled “Structural Basis for G9a-Like Protein LysineMethyltransferase Inhibition by Bix-01294”, a ligand identified in Liuet al. (J Med Chem 2009, 52, 7950-7953) titled “Discovery of a2,4-Diamino-7-Aminoalkoxyquinazoline as a Potent and Selective Inhibitorof Histone Lysine Methyltransferase G9a”, azacitidine, decitabine, or ananalog thereof.

In certain embodiments, the Targeting Ligand is an angiogenesisinhibitor. Non-limiting examples of angiogenesis inhibitors include:GA-1, estradiol, testosterone, ovalicin, fumagillin, and analogsthereof.

In certain embodiments, the Targeting Ligand is an immunosuppressivecompound. Non-limiting examples of immunosuppressive compounds include:AP21998, hydrocortisone, prednisone, prednisolone, methylprednisolone,beclometasone dipropionate, methotrexate, ciclosporin, tacrolimus,actinomycin, and analogues thereof.

In certain embodiments, the Targeting Ligand is an Aryl HydrocarbonReceptor (AHR) ligand. Non-limiting examples of AHR ligands include:apigenin, SR1, LGC006, and analogues thereof.

In certain embodiments, the Targeting Ligand is a MerTK or Mer Targetingligand. Non-limiting examples of MerTK Targeting Ligands are included inWO2013/177168 and WO2014/085225, both titled “Pyrimidine Compounds forthe Treatment of Cancer” filed by Wang, et al.

In certain embodiments, the Targeting Ligand is an EGFR ligand. Incertain embodiments the Targeting Ligand is an EGRF ligand selected fromAfatinib, Dacomitinib, Neratinib, Poziotinib, and Canertinib, orderivatives thereof.

In certain embodiments, the Targeting Ligand is a FLT3 Ligand. Incertain embodiments, the Targeting Ligand is a FLT3 ligand selected fromTandutinib, Lestaurtinib, Sorafenib, Midostaurin, Quizartinib, andCrenolanib.

In certain embodiments, the Targeting Ligand is a RAF inhibitor. Incertain embodiments the Targeting Ligand is a RAF inhibitor selectedfrom Dabrafenib, Regorafenib, and Vemurafenib. In certain embodimentsthe Targeting Ligand is a cRAF inhibitor.

In some embodiments, the Targeting Ligand is an Ubc9 SUMO E2 ligase 5F6DTargeting Ligand including but not limited to those described in“Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9.” byHewitt, W. M., et. al. (2016) Angew. Chem. Int. Ed. Engl. 55: 5703-5707

In another embodiment, the Targeting Ligand is a Tank1 Targeting Ligandincluding but not limited to those described in “Structure of humantankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939.”Kirby, C. A., Cheung, A., Fazal, A., Shultz, M. D., Stams, T, (2012)Acta Crystallogr., Sect. F 68: 115-118; and “Structure-EfficiencyRelationship of [1,2,4]Triazol-3-ylamines as Novel NicotinamideIsosteres that Inhibit Tankyrases.” Shultz, M. D., et al. (2013) J. Med.Chem. 56: 7049-7059.

In another embodiment, the Targeting Ligand is a SH2 domain of pp60 SrcTargeting Ligand including but not limited to those described in“Requirements for Specific Binding of Low Affinity Inhibitor Fragmentsto the SH2 Domain of pp60Src Are Identical to Those for High AffinityBinding of Full Length Inhibitors,” Gudrun Lange, et al., J. Med. Chem.2003, 46, 5184-5195.

In another embodiment, the Targeting Ligand is a Sec7 domain TargetingLigand including but not limited to those described in “The LysosomalProtein Saposin B Binds Chloroquine,” Huta, B. P., et al., (2016)Chemmedchem 11: 277.

In another embodiment, the Targeting Ligand is a Saposin-B TargetingLigand including but not limited to those described in “The structure ofcytomegalovirus immune modulator UL 141 highlights structural Ig-foldversatility for receptor binding” I. Nemcovicova and D. M. Zajonc ActaCryst. (2014). D70, 851-862.

In another embodiment, the Targeting Ligand is a Protein S100-A7 2OWSTargeting Ligand including but not limited to those described in “2WOSSTRUCTURE OF HUMAN S100A7 IN COMPLEX WITH 2,6 ANS” DOI:10.2210/pdb2wos/pdb; and “Identification and Characterization of BindingSites on S100A7, a Participant in Cancer and Inflammation Pathways.”Leon, R., Murray, et al., (2009) Biochemistry 48: 10591-10600.

In another embodiment, the Targeting Ligand is a Phospholipase A2Targeting Ligand including but not limited to those described in“Structure-based design of the first potent and selective inhibitor ofhuman non-pancreatic secretory phospholipase A2 “Schevitz, R. W., etal., Nat. Struct. Biol. 1995, 2, 458-465.

In another embodiment, the Targeting Ligand is a PHIP Targeting Ligandincluding but not limited to those described in “A Poised FragmentLibrary Enables Rapid Synthetic Expansion Yielding the First ReportedInhibitors of PHIP(2), an Atypical Bromodomain” Krojer, T.; et al. Chem.Sci. 2016, 7, 2322-2330.

In another embodiment, the Targeting Ligand is a PDZ Targeting Ligandincluding but not limited to those described in “Discovery ofLow-Molecular-Weight Ligands for the AF6 PDZ Domain” Mangesh Joshi, etal. Angew. Chem. Int. Ed. 2006, 45, 3790-3795.

In another embodiment, the Targeting Ligand is a PARP15 Targeting Ligandincluding but not limited to those described in “Structural Basis forLack of ADP-ribosyltransferase Activity in Poly(ADP-ribose)Polymerase-13/Zinc Finger Antiviral Protein.” Karlberg, T., et al.,(2015) J. Biol. Chem. 290: 7336-7344.

In another embodiment, the Targeting Ligand is a PARP14 Targeting Ligandincluding but not limited to those described in “Discovery of Ligandsfor ADP-Ribosyltransferases via Docking-Based Virtual Screening.”Andersson, C. D., et al., (2012) J. Med. Chem. 55: 7706-7718;“Family-wide chemical profiling and structural analysis of PARP andtankyrase inhibitors.”Wahlberg, E., et al. (2012) Nat. Biotechnol. 30:283-288; “Discovery of Ligands for ADP-Ribosyltransferases viaDocking-Based Virtual Screening. “Andersson, C. D., et al. (2012) J.Med. Chem. 55: 7706-7718.

In another embodiment, the Targeting Ligand is a MTH1 Targeting Ligandincluding but not limited to those described in “MTH1 inhibitioneradicates cancer by preventing sanitation of the dNTP pool” Helge Gad,et. al. Nature, 2014, 508, 215-221.

In another embodiment, the Targeting Ligand is a mPGES-1 TargetingLigand including but not limited to those described in “CrystalStructures of mPGES-1 Inhibitor Complexes Form a Basis for the RationalDesign of Potent Analgesic and Anti-Inflammatory Therapeutics.” Luz, J.G., et al., (2015) J. Med. Chem. 58: 4727-4737.

In another embodiment, the Targeting Ligand is aFLAP-5-lipoxygenase-activating protein Targeting Ligand including butnot limited to those described in “Crystal structure of inhibitor-boundhuman 5-lipoxygenase-activating protein, ” Ferguson, A. D., McKeever, B.M., Xu, S., Wisniewski, D., Miller, D. K., Yamin, T. T., Spencer, R. H.,Chu, L., Ujjainwalla, F., Cunningham, B. R., Evans, J. F., Becker, J. W.(2007) Science 317: 510-512.

In another embodiment, the Targeting Ligand is a FA Binding ProteinTargeting Ligand including but not limited to those described in “AReal-World Perspective on Molecular Design.” Kuhn, B.; et al. J. Med.Chem. 2016, 59, 4087-4102.

In another embodiment, the Targeting Ligand is a BCL2 Targeting Ligandincluding but not limited to those described in “ABT-199, a potent andselective BCL-2 inhibitor, achieves antitumor activity while sparingplatelets.” Souers, A. J., et al. (2013) NAT. MED. (N.Y.) 19: 202-208.

In another embodiment, the Targeting Ligand is a NF2L2 Targeting Ligand.

In another embodiment, the Targeting Ligand is a CTNNB1 TargetingLigand.

In another embodiment, the Targeting Ligand is a CBLB Targeting Ligand.

In another embodiment, the Targeting Ligand is a BCL6 Targeting Ligand.

In another embodiment, the Targeting Ligand is a RASK Targeting Ligand.

In another embodiment, the Targeting Ligand is a TNIK Targeting Ligand.

In another embodiment, the Targeting Ligand is a MEN1 Targeting Ligand.

In another embodiment, the Targeting Ligand is a PI3Ka Targeting Ligand.

In another embodiment, the Targeting Ligand is a IDO1 Targeting Ligand.

In another embodiment, the Targeting Ligand is a MCL1 Targeting Ligand.

In another embodiment, the Targeting Ligand is a PTPN2 Targeting Ligand.

In another embodiment, the Targeting Ligand is a HER2 Targeting Ligand.

In another embodiment, the Targeting Ligand is an EGFR Targeting Ligand.In one embodiment the Targeting Ligand is selected from erlotinib(Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib(CO-1686), osimertinib (Tagrisso), olmutinib (Olita), naquotinib(ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib(BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045,tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib(XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, anddacomitinib (PF-00299804; Pfizer). The linker can be placed on theseTargeting Ligands in any location that does not interfere with theLigands binding to EGFR. Non-limiting examples of Linker bindinglocations are provided in the below tables. In one embodiment, the EGFRTargeting Ligand binds the L858R mutant of EGFR. In another embodiment,the EGFR Targeting Ligand binds the T790M mutant of EGFR. In anotherembodiment, the EGFR Targeting Ligand binds the C797G or C797S mutant ofEGFR. In one embodiment, the EGFR Targeting Ligand is selected fromerlotinib, gefitinib, afatinib, neratinib, and dacomitinib and binds theL858R mutant of EGFR. In another embodiment, the EGFR Targeting Ligandis selected from osimertinib, rociletinib, olmutinib, naquotinib,nazartinib, PF-06747775, Icotinib, Neratinib, Avitinib, Tarloxotinib,PF-0645998, Tesevatinib, Transtinib, WZ-3146, WZ8040, and CNX-2006 andbinds the T790M mutant of EGFR. In another embodiment, the EGFRTargeting Ligand is EAI045 and binds the C797G or C797S mutant of EGFR.

In one embodiment, the protein target and Targeting Ligand pair arechosen by screening a library of ligands. Such a screening isexemplified in “Kinase Inhibitor Profiling Reveals UnexpectedOpportunities to Inhibit Disease-Associated Mutant Kinases” by Duong-Lyet al.; Cell Reports 14, 772-781 Feb. 2, 2016.

In one embodiment, the protein target and Targeting Ligand pair arediscovered by screening promiscuous kinase binding ligands forcontext-specific degradation. Non-limiting examples of targeting ligandsare shown below and are found in “Optimized Chemical Proteomics Assayfor Kinase Inhibitor Profiling” Guillaume Médard, Fiona Pachl, BenjaminRuprecht, Susan Klaeger, Stephanie Heinzlmeir, Dominic Helm, HuichaoQiao, Xin Ku, Mathias Wilhelm, Thomas Kuehne, Zhixiang Wu, AntjeDittmann, Carsten Hopf, Karl Kramer, and Bernhard Kuster J. ProteomeRes., 2015, 14(3), pp 1574-1586:

These ligands can be attached to linkers as shown below:

wherein:R is the point at which the Linker is attached.

According to the present invention, the Targeting Ligand can becovalently bound to the Linker in any manner that achieves the desiredresults of the Degronimer for therapeutic use. In certain non-limitingembodiments, the Targeting Ligand is bound to the Linker with afunctional group that does not adversely affect the binding of theLigand to the Target Protein. The attachment points below are exemplaryin nature and one of ordinary skill in the art would be able todetermine different appropriate attachment points.

The non-limiting compounds described below exemplify some of the membersof these types of small molecule Targeting Ligands. In the Tables below,R is the point at which the Linker is attached to the Targeting Ligand.

In certain embodiments, the Targeting Ligand is a compound of FormulaTL-I:

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is S or C═C;

A² is NRa⁵ or O;

nn1 is 0, 1, or 2;

each Ra¹ is independently C₁-C₃ alkyl, (CH₂)₀₋₃—CN, (CH₂)₀₋₃-halogen,(CH₂)₀₋₃—OH, (CH₂)₀₋₃—C₁-C₃ alkoxy, or R;

Ra² is H, C₁-C₆ alkyl, (CH₂)₀₋₃-heterocyclyl, (CH₂)₀₋₃-phenyl, or R,wherein the heterocyclyl comprises one saturated 5- or 6-membered ringand 1-2 heteroatoms selected from N, O, and S and is optionallysubstituted with C₁-C₃ alkyl and wherein the phenyl is optionallysubstituted with C₁-C₃ alkyl, CN, halogen, OH, C₁-C₃ alkoxy;

nn2 is 0, 1, 2, or 3;

each Ra³ is independently C₁-C₃ alkyl, (CH₂)₀₋₃—CN, (CH₂)₀₋₃-halogen, orR;

Ra⁴ is C₁-C₃ alkyl;

Ra⁵ is H or C₁-C₃ alkyl; and

R is the point at which the Linker is attached.

wherein the compound of Formula TL-I is substituted with only one R.

In certain embodiments, the Targeting Ligand is a compound of FormulaTL-VIII or Formula TL-IX:

wherein the compound of Formula TL-VIII or TL-IX is substituted withonly one R.

In certain embodiments,

In certain embodiments,

In certain embodiments, A¹ is S.

In certain embodiments, A¹ is C═C.

In certain embodiments, A² is NRa⁵. In further embodiments, Ra⁵ is H. Inother embodiments, Ra⁵ is C₁-C₃ alkyl (e.g., methyl, ethyl, propyl, ori-propyl). In further embodiments, Ra⁵ is methyl.

In certain embodiments, A² is O.

In certain embodiments, nn1 is 0.

In certain embodiments, nn1 is 1.

In certain embodiments, nn1 is 2.

In certain embodiments, at least one Ra¹ is C₁-C₃ alkyl (e.g., methyl,ethyl, propyl, or i-propyl). In further embodiments, at least one Ra¹ ismethyl. In further embodiments, two Ra¹ are methyl.

In certain embodiments, at least one Ra¹ is CN, (CH₂)—CN, (CH₂)₂—CN, or(CH₂)₃—CN. In further embodiments, at least one Ra¹ is (CH₂)—CN.

In certain embodiments, at least one Ra¹ is halogen (e.g., F, C₁, orBr), (CH₂)-halogen, (CH₂)₂-halogen, or (CH₂)₃-halogen. In furtherembodiments, at least one Ra¹ is C₁, (CH₂)—Cl, (CH₂)₂—Cl, or (CH₂)₃—Cl.

In certain embodiments, at least one Ra¹ is OH, (CH₂)—OH, (CH₂)₂—OH, or(CH₂)₃—OH.

In certain embodiments, at least one Ra¹ is C₁-C₃ alkoxy (e.g., methoxy,ethoxy, or propoxy), (CH₂)—C₁-C₃ alkoxy, (CH₂)₂—C₁-C₃ alkoxy, or(CH₂)₃—C₁-C₃ alkoxy. In certain embodiments, at least one Ra¹ ismethoxy.

In further embodiments, Ra⁵ is H. In other embodiments, Ra⁵ is C₁-C₃alkyl (e.g., methyl, ethyl, propyl, or i-propyl).

In further embodiments, Ra⁵ is H. In other embodiments, Ra⁵ is C₁-C₃alkyl (e.g., methyl, ethyl, propyl, or i-propyl). In other embodiments,Ra⁵ is methyl.

In certain embodiments, one Ra¹ is R.

In certain embodiments, Ra² is H.

In certain embodiments, Ra² is straight-chain C₁-C₆ or branched C₃-C₆alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, or hexyl). In further embodiments, Ra² is methyl, ethyl, ort-butyl.

In certain embodiments, Ra² is heterocyclyl, (CH₂)-heterocyclyl,(CH₂)₂-heterocyclyl, or (CH₂)₃-heterocyclyl. In further embodiments, Ra²is (CH₂)₃-heterocyclyl. In further embodiments, the heterocyclyl isselected from pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,piperazinyl, hexahydropyrimidinyl, morpholinyl, and thiomorpholinyl. Infurther embodiments, the heterocyclyl is piperazinyl.

In certain embodiments, the heterocyclyl is substituted with C₁-C₃ alkyl(e.g., methyl, ethyl, propyl, or i-propyl).

In certain embodiments, Ra² is phenyl, (CH₂)-phenyl, (CH₂)₂-phenyl, or(CH₂)₃-phenyl. In further embodiments, Ra² is phenyl.

In certain embodiments, the phenyl is substituted with C₁-C₃ alkyl(e.g., methyl, ethyl, propyl, or i-propyl). In certain embodiments, thephenyl is substituted with CN. In certain embodiments, the phenyl issubstituted with halogen (e.g., F, Cl, or Br). In certain embodiments,the phenyl is substituted with OH. In certain embodiments, the phenyl issubstituted with C₁-C₃ alkoxy (e.g., methoxy, ethoxy, or propoxy).

In certain embodiments, Ra² is R.

In certain embodiments, nn2 is 0.

In certain embodiments, nn2 is 1.

In certain embodiments, nn2 is 2.

In certain embodiments, nn2 is 3.

In certain embodiments, at least one Ra³ is C₁-C₃ alkyl (e.g., methyl,ethyl, propyl, or i-propyl). In further embodiments, at least one Ra³ ismethyl.

In certain embodiments, at least one Ra³ is CN, (CH₂)—CN, (CH₂)₂—CN, or(CH₂)₃—CN. In further embodiments, at least one Ra³ is CN.

In certain embodiments, at least one Ra³ is halogen (e.g., F, Cl, orBr), (CH₂)-halogen, (CH₂)₂-halogen, or (CH₂)₃-halogen. In furtherembodiments, at least one Ra³ is Cl, (CH₂)—Cl, (CH₂)₂—Cl, or (CH₂)₃—Cl.In further embodiments, at least one Ra³ is Cl.

In certain embodiments, one Ra³ is R.

In further embodiments, Ra⁵ is H. In other embodiments, Ra⁵ is C₁-C₃alkyl (e.g., methyl, ethyl, propyl, or i-propyl).

In certain embodiments, Ra⁴ is C₁-C₃ alkyl (e.g., methyl, ethyl, propyl,or i-propyl). In further embodiments, Ra⁴ is methyl.

In certain embodiments, Ra⁵ is H.

In certain embodiments, Ra⁵ is C₁-C₃ alkyl (e.g., methyl, ethyl, propyl,or i-propyl). In further embodiments, Ra⁵ is methyl.

In certain embodiments,

and A¹ is S.

In certain embodiments,

and A¹ is C═C.

In certain embodiments,

and A¹ is C═C.

In certain embodiments, A² is NH, and Ra² is (CH₂)₀₋₃-heterocyclyl. Infurther embodiments, Ra² is (CH₂)₃-heterocyclyl.

In certain embodiments, A² is NH, and Ra² is (CH₂)₀₋₃-phenyl. In furtherembodiments, Ra² is phenyl. In further embodiments, the phenyl issubstituted with OH.

In certain embodiments, A² is NH, and Ra² is R.

In certain embodiments, A² is NH, and Ra² is H or C₁-C₆ alkyl. Infurther embodiments, Ra² is C₁-C₄ alkyl.

In certain embodiments, A² is O, and Ra² is H or C₁-C₆ alkyl. In furtherembodiments, Ra² is C₁-C₄ alkyl.

III. Methods of Treatment

The compound of Formulas I, II, III, IV, V, VI and VII can be used in aneffective amount to treat a host with any of the disorders describedherein, including a human, in need thereof, optionally in apharmaceutically acceptable carrier. In certain embodiments, the methodcomprises administering an effective amount of the active compound orits salt as described herein, optionally including a pharmaceuticallyacceptable excipient, carrier, adjuvant, i.e., a pharmaceuticallyacceptable composition, optionally in combination or alternation withanother bioactive agent or combination of agents.

The compound of Formula I, II, V or VII or a pharmaceutically acceptablesalt thereof as described herein can be used to degrade a Target Proteinwhich is a mediator of the disorder affecting the patient, such as ahuman. The reduction in the Target Protein level afforded by the FormulaI, II, V or VII Degronimers of the present invention provides treatmentof the implicated disease state or condition, which is modulated throughthe Target Protein by lowering the level of that protein in the cell,e.g., cell of a patient. The term “disease state or condition” when usedin connection with a Formula I, II, V or VII compound is meant to referto any disease state or condition wherein protein dysregulation occursthat involves the selected Target Protein and where degradation of suchprotein in a patient may provide beneficial therapy or relief ofsymptoms to a patient in need thereof. In certain instances, the diseasestate or condition may be cured.

The compounds of Formula I, II, V or VII are useful as therapeuticagents when administered in an effective amount to a host, including ahuman, to treat a tumor, cancer (solid, non-solid, diffuse,hematological, etc), abnormal cellular proliferation, immune disorder,inflammatory disorder, blood disorder, a myelo- or lymphoproliferativedisorder such as B- or T-cell lymphomas, multiple myeloma, breastcancer, prostate cancer, AML, ALL, ACL, lung cancer, pancreatic cancer,colon cancer, skin cancer, melanoma, Waldenstrom's macroglobulinemia,Wiskott-Aldrich syndrome, or a post-transplant lymphoproliferativedisorder; an autoimmune disorder, for example, Lupus, Crohn's Disease,Addison disease, Celiac disease, dermatomyositis, Graves disease,thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis,or type I diabetes; a disease of cardiologic malfunction, includinghypercholesterolemia; an infectious disease, including a viral and/orbacterial infection; an inflammatory condition, including asthma,chronic peptic ulcers, tuberculosis, rheumatoid arthritis,periodontitis, ulcerative colitis, or hepatitis.

The term “disease state or condition” when used in connection with aFormula III, IV or VI compound, for example, refers to any therapeuticindication which can be treated by decreasing the activity of cereblonor a cereblon-containing E3 Ligase, including but not limited to usesknown for the cereblon binders thalidomide, pomalidomide orlenalidomide. Nonlimiting examples of uses for cereblon binders aremultiple myeloma, a hematological disorder such as myelodysplasticsyndrome, cancer, tumor, abnormal cellular proliferation, breast cancer,prostate cancer, AML, ALL, ACL, lung cancer, pancreatic cancer, coloncancer, skin cancer, melanoma, HIV/AIDS, HBV, HCV, hepatitis, Crohn'sdisease, sarcoidosis, graft-versus-host disease, rheumatoid arthritis,Behcet's disease, tuberculosis, and myelofibrosis. Other indicationsinclude a myelo- or lymphoproliferative disorder such as B- or T-celllymphomas, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, ora post-transplant lymphoproliferative disorder; an immune disorder,including autoimmune disorders for example as Lupus, Addison disease,Celiac disease, dermatomyositis, Graves disease, thyroiditis, multiplesclerosis, pernicious anemia, arthritis, and in particular rheumatoidarthritis, or type I diabetes; a disease of cardiologic malfunction,including hypercholesterolemia; an infectious disease, including viraland/or bacterial infection, as described generally herein; aninflammatory condition, including asthma, chronic peptic ulcers,tuberculosis, rheumatoid arthritis, periodontitis and ulcerativecolitis.

In certain embodiments, the present invention provides theadministration of an effective amount of a compound to treat a patient,for example, a human, having an infectious disease, wherein the therapytargets a Target Protein of the infectious agent or host (Formulas I,II, V or VII), or acts via binding to cereblon or its E3 ligase(Formulas III, IV and VI) optionally in combination with anotherbioactive agent. The disease state or condition may be caused by amicrobial agent or other exogenous agent such as a virus (asnon-limiting examples, HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola,Flavivirus, Pestivirus, Rotavirus, Influenza, Coronavirus, EBV, viralpneumonia, drug-resistant viruses, Bird flu, RNA virus, DNA virus,adenovirus, poxvirus, Picornavirus, Togavirus, Orthomyxovirus,Retrovirus or Hepadnovirus), bacteria (including but not limited toGram-negative, Gram-positive, Atypical, Staphylococcus, Streptococcus,E. Coli, Salmonella, Helicobacter pylori, meningitis, gonorrhea,Chlamydiaceae, Mycoplasmataceae, etc), fungus, protozoa, helminth,worms, prion, parasite, or other microbe.

In certain embodiments, the condition treated with a compound of thepresent invention is a disorder related to abnormal cellularproliferation. Abnormal cellular proliferation, notablyhyperproliferation, can occur as a result of a wide variety of factors,including genetic mutation, infection, exposure to toxins, autoimmunedisorders, and benign or malignant tumor induction.

There are a number of skin disorders associated with cellularhyperproliferation. Psoriasis, for example, is a benign disease of humanskin generally characterized by plaques covered by thickened scales. Thedisease is caused by increased proliferation of epidermal cells ofunknown cause. Chronic eczema is also associated with significanthyperproliferation of the epidermis. Other diseases caused byhyperproliferation of skin cells include atopic dermatitis, lichenplanus, warts, pemphigus vulgaris, actinic keratosis, basal cellcarcinoma and squamous cell carcinoma.

Other hyperproliferative cell disorders include blood vesselproliferation disorders, fibrotic disorders, autoimmune disorders,graft-versus-host rejection, tumors and cancers.

Blood vessel proliferative disorders include angiogenic and vasculogenicdisorders. Proliferation of smooth muscle cells in the course ofdevelopment of plaques in vascular tissue cause, for example,restenosis, retinopathies and atherosclerosis. Both cell migration andcell proliferation play a role in the formation of atheroscleroticlesions.

Fibrotic disorders are often due to the abnormal formation of anextracellular matrix. Examples of fibrotic disorders include hepaticcirrhosis and mesangial proliferative cell disorders. Hepatic cirrhosisis characterized by the increase in extracellular matrix constituentsresulting in the formation of a hepatic scar. Hepatic cirrhosis cancause diseases such as cirrhosis of the liver. An increasedextracellular matrix resulting in a hepatic scar can also be caused byviral infection such as hepatitis. Lipocytes appear to play a major rolein hepatic cirrhosis.

Mesangial disorders are brought about by abnormal proliferation ofmesangial cells. Mesangial hyperproliferative cell disorders includevarious human renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic micro-angiopathysyndromes, transplant rejection, and glomerulopathies.

Another disease with a proliferative component is rheumatoid arthritis.Rheumatoid arthritis is generally considered an autoimmune disease thatis thought to be associated with activity of autoreactive T cells, andto be caused by autoantibodies produced against collagen and IgE.

Other disorders that can include an abnormal cellular proliferativecomponent include Bechet's syndrome, acute respiratory distress syndrome(ARDS), ischemic heart disease, post-dialysis syndrome, leukemia,acquired immune deficiency syndrome, vasculitis, lipid histiocytosis,septic shock and inflammation in general.

Cutaneous contact hypersensitivity and asthma are just two examples ofimmune responses that can be associated with significant morbidity.Others include atopic dermatitis, eczema, Sjogren's Syndrome, includingkeratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopeciaareata, allergic responses due to arthropod bite reactions, Crohn'sdisease, aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis,ulcerative colitis, cutaneous lupus erythematosus, scleroderma,vaginitis, proctitis, and drug eruptions. These conditions may result inany one or more of the following symptoms or signs: itching, swelling,redness, blisters, crusting, ulceration, pain, scaling, cracking, hairloss, scarring, or oozing of fluid involving the skin, eye, or mucosalmembranes.

In atopic dermatitis, and eczema in general, immunologically mediatedleukocyte infiltration (particularly infiltration of mononuclear cells,lymphocytes, neutrophils, and eosinophils) into the skin importantlycontributes to the pathogenesis of these diseases. Chronic eczema alsois associated with significant hyperproliferation of the epidermis.Immunologically mediated leukocyte infiltration also occurs at sitesother than the skin, such as in the airways in asthma and in the tearproducing gland of the eye in keratoconjunctivitis sicca.

In one non-limiting embodiment compounds of the present invention areused as topical agents in treating contact dermatitis, atopicdermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome,including keratoconjunctivitis sicca secondary to Sjogren's Syndrome,alopecia areata, allergic responses due to arthropod bite reactions,Crohn's disease, aphthous ulcer, iritis, conjunctivitis,keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma,cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, anddrug eruptions. The novel method may also be useful in reducing theinfiltration of skin by malignant leukocytes in diseases such as mycosisfungoides. These compounds can also be used to treat anaqueous-deficient dry eye state (such as immune mediatedkeratoconjunctivitis) in a patient suffering therefrom, by administeringthe compound topically to the eye.

Disease states which may be treated according to the present inventioninclude, for example, asthma, autoimmune diseases such as multiplesclerosis, various cancers, ciliopathies, cleft palate, diabetes, heartdisease, hypertension, inflammatory bowel disease, mental retardation,mood disorder, obesity, refractive error, infertility, Angelmansyndrome, Canavan disease, Coeliac disease, Charcot-Marie-Tooth disease,Cystic fibrosis, Duchenne muscular dystrophy, Haemochromatosis,Haemophilia, Klinefelter's syndrome, Neurofibromatosis, Phenylketonuria,Polycystic kidney disease 1 (PKD1) or 2 (PKD2) Prader-Willi syndrome,Sickle-cell disease, Tay-Sachs disease, Turner syndrome.

Further disease states or conditions which may be treated by thedisclosed compounds according to the present invention includeAlzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig'sdisease), Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attentiondeficit hyperactivity disorder, Autism, Bipolar disorder, Chronicfatigue syndrome, Chronic obstructive pulmonary disease, Crohn'sdisease, Coronary heart disease, Dementia, Depression, Diabetes mellitustype 1, Diabetes mellitus type 2, Epilepsy, Guillain-Barré syndrome,Irritable bowel syndrome, Lupus, Metabolic syndrome, Multiple sclerosis,Myocardial infarction, Obesity, Obsessive-compulsive disorder, Panicdisorder, Parkinson's disease, Psoriasis, Rheumatoid arthritis,Sarcoidosis, Schizophrenia, Stroke, Thromboangiitis obliterans, Tourettesyndrome, Vasculitis.

Still additional disease states or conditions which can be treated bythe disclosed compounds according to the present invention includeaceruloplasminemia, Achondrogenesis type II, achondroplasia,Acrocephaly, Gaucher disease type 2, acute intermittent porphyria,Canavan disease, Adenomatous Polyposis Coli, ALA dehydratase deficiency,adenylosuccinate lyase deficiency, Adrenogenital syndrome,Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency,Alkaptonuria, Alexander disease, Alkaptonuric ochronosis, alpha1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema,amyotrophic lateral sclerosis Alstrom syndrome, Alexander disease,Amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabrydisease, androgen insensitivity syndrome, Anemia Angiokeratoma CorporisDiffusum, Angiomatosis retinae (von Hippel-Lindau disease) Apertsyndrome, Arachnodactyly (Marfan syndrome), Stickler syndrome,Arthrochalasis multiplex congenital (Ehlers-Danlossyndrome#arthrochalasia type) ataxia telangiectasia, Rett syndrome,primary pulmonary hypertension, Sandhoff disease, neurofibromatosis typeII, Beare-Stevenson cutis gyrata syndrome, Mediterranean fever,familial, Benjamin syndrome, beta-thalassemia, Bilateral AcousticNeurofibromatosis (neurofibromatosis type II), factor V Leidenthrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloomsyndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome(Turner syndrome), Bourneville disease (tuberous sclerosis), priondisease, Birt-Hogg-Dubé syndrome, Brittle bone disease (osteogenesisimperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome),Bronze Diabetes/Bronzed Cirrhosis (hemochromatosis), Bulbospinalmuscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoproteinlipase deficiency), CGD Chronic granulomatous disorder, Campomelicdysplasia, biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cridu chat, CAVD (congenital absence of the vas deferens), Caylorcardiofacial syndrome (CBAVD), CEP (congenital erythropoieticporphyria), cystic fibrosis, congenital hypothyroidism, Chondrodystrophysyndrome (achondroplasia), otospondylomegaepiphyseal dysplasia,Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome,Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome,(familial adenomatous polyposis), Congenital erythropoietic porphyria,Congenital heart disease, Methemoglobinemia/Congenitalmethaemoglobinaemia, achondroplasia, X-linked sideroblastic anemia,Connective tissue disease, Conotruncal anomaly face syndrome, Cooley'sAnemia (beta-thalassemia), Copper storage disease (Wilson's disease),Copper transport disease (Menkes disease), hereditary coproporphyria,Cowden syndrome, Craniofacial dysarthrosis (Crouzon syndrome),Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowdensyndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy),Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy,Duchenne and Becker types (DBMD), Usher syndrome, Degenerative nervediseases including de Grouchy syndrome and Dejerine-Sottas syndrome,developmental disabilities, distal spinal muscular atrophy, type V,androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbedisease), Di George's syndrome, Dihydrotestosterone receptor deficiency,androgen insensitivity syndrome, Down syndrome, Dwarfism, erythropoieticprotoporphyria Erythroid 5-aminolevulinate synthetase deficiency,Erythropoietic porphyria, erythropoietic protoporphyria, erythropoieticuroporphyria, Friedreich's ataxia-familial paroxysmal polyserositis,porphyria cutanea tarda, familial pressure sensitive neuropathy, primarypulmonary hypertension (PPH), Fibrocystic disease of the pancreas,fragile X syndrome, galactosemia, genetic brain disorders, Giant cellhepatitis (Neonatal hemochromatosis), Gronblad-Strandberg syndrome(pseudoxanthoma elasticum), Gunther disease (congenital erythropoieticporphyria), haemochromatosis, Hallgren syndrome, sickle cell anemia,hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease(von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilfordprogeria syndrome (progeria), Hyperandrogenism, Hypochondroplasia,Hypochromic anemia, Immune system disorders, including X-linked severecombined immunodeficiency, Insley-Astley syndrome, Jackson-Weisssyndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weisssyndrome, Kidney diseases, including hyperoxaluria, Klinefelter'ssyndrome, Kniest dysplasia, Lacunar dementia, Langer-Saldinoachondrogenesis, ataxia telangiectasia, Lynch syndrome,Lysyl-hydroxylase deficiency, Machado-Joseph disease, Metabolicdisorders, including Kniest dysplasia, Marfan syndrome, Movementdisorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome,Multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeneychondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffersyndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystickidney disease, polyostotic fibrous dysplasia (McCune-Albrightsyndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome,hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome),primary pulmonary hypertension, primary senile degenerative dementia,prion disease, progeria (Hutchinson Gilford Progeria Syndrome),progressive chorea, chronic hereditary (Huntington) (Huntington'sdisease), progressive muscular atrophy, spinal muscular atrophy,propionic acidemia, protoporphyria, proximal myotonic dystrophy,pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb(retinoblastoma), Recklinghausen disease (neurofibromatosis type I),Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rettsyndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levysyndrome, severe achondroplasia with developmental delay and acanthosisnigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, andadrenal gland (SBLA) syndrome, sclerosis tuberose (tuberous sclerosis),SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SEDStrudwick (spondyloepimetaphyseal dysplasia, Strudwick type), SEDc(spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type(spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen syndrome,Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South-Africangenetic porphyria (variegate porphyria), infantile-onset ascendinghereditary spastic paralysis, Speech and communication disorders,sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Sticklersyndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterindeficiency, beta-thalassemia, Thyroid disease, Tomaculous neuropathy(hereditary neuropathy with liability to pressure palsies).

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue(solid) or cells (non-solid) that grow by cellular proliferation, oftenmore rapidly than normal and continues to grow after the stimuli thatinitiated the new growth cease. Malignant neoplasms show partial orcomplete lack of structural organization and functional coordinationwith the normal tissue and most invade surrounding tissues, canmetastasize to several sites, are likely to recur after attemptedremoval and may cause the death of the patient unless adequatelytreated. As used herein, the term neoplasia is used to describe allcancerous disease states and embraces or encompasses the pathologicalprocess associated with malignant hematogenous, ascitic and solidtumors. Exemplary cancers which may be treated by the present disclosedcompounds either alone or in combination with at least one additionalanti-cancer agent include squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas,cancer of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using the disclosed compounds according to the present inventioninclude, for example, acute granulocytic leukemia, acute lymphocyticleukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma,adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer,anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma,Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer,bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stemglioma, breast cancer, triple (estrogen, progesterone and HER-2)negative breast cancer, double negative breast cancer (two of estrogen,progesterone and HER-2 are negative), single negative (one of estrogen,progesterone and HER-2 is negative), estrogen-receptor positive,HER2-negative breast cancer, estrogen receptor-negative breast cancer,estrogen receptor positive breast cancer, metastatic breast cancer,luminal A breast cancer, luminal B breast cancer, Her2-negative breastcancer, HER2-positive or negative breast cancer, progesteronereceptor-negative breast cancer, progesterone receptor-positive breastcancer, recurrent breast cancer, carcinoid tumors, cervical cancer,cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), colon cancer, colorectal cancer,craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuseastrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer,ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma,extrahepatic bile duct cancer, eye cancer, fallopian tube cancer,fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinalcancer, gastrointestinal carcinoid cancer, gastrointestinal stromaltumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma,hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkinlymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC),infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC),intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltratingbreast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidneycancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases,leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma insitu, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma,male breast cancer, medullary carcinoma, medulloblastoma, melanoma,meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma,mesenchymous, mesothelioma metastatic breast cancer, metastatic melanomametastatic squamous neck cancer, mixed gliomas, monodermal teratoma,mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma,Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer,nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors(NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oatcell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oralcancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germcell tumor, ovarian primary peritoneal carcinoma, ovarian sex cordstromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma,paranasal sinus cancer, parathyroid cancer, pelvic cancer, penilecancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,pheochromocytoma, pilocytic astrocytoma, pineal region tumor,pineoblastoma, pituitary gland cancer, primary central nervous system(CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma,renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, softtissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, smallcell lung cancer (SCLC), small intestine cancer, spinal cancer, spinalcolumn cancer, spinal cord cancer, squamous cell carcinoma, stomachcancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throatcancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsilcancer, transitional cell cancer, tubal cancer, tubular carcinoma,undiagnosed cancer, ureteral cancer, urethral cancer, uterineadenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-celllineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, AdultT-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma,Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia(JMML), acute promyelocytic leukemia (a subtype of AML), large granularlymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large Bcell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large Bcell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenicmarginal zone lymphoma (SMZL); intravascular large B-cell lymphoma;primary effusion lymphoma; or lymphomatoid granulomatosis; B-cellprolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacyticlymphoma; heavy chain diseases, for example, Alpha heavy chain disease,Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma,solitary plasmacytoma of bone; extraosseous plasmacytoma; primarycutaneous follicle center lymphoma, T cell/histocyte rich large B-celllymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus(EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-celllymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma,plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associatedmulticentric, Castleman disease; B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma, or B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma.

IV. Combination Therapy

The disclosed compounds of Formula I, II, III, IV, V, VI or VII can beused in an effective amount alone or in combination with anothercompound of the present invention or another bioactive agent to treat ahost such as a human with a disorder as described herein.

The disclosed compounds described herein can be used in an effectiveamount alone or in combination with another compound of the presentinvention or another bioactive agent to treat a host such as a humanwith a disorder as described herein.

The term “bioactive agent” is used to describe an agent, other than theselected compound according to the present invention, which can be usedin combination or alternation with a compound of the present inventionto achieve a desired result of therapy. In one embodiment, the compoundof the present invention and the bioactive agent are administered in amanner that they are active in vivo during overlapping time periods, forexample, have time-period overlapping Cmax, Tmax, AUC or otherpharmacokinetic parameter. In another embodiment, the compound of thepresent invention and the bioactive agent are administered to a host inneed thereof that do not have overlapping pharmacokinetic parameter,however, one has a therapeutic impact on the therapeutic efficacy of theother.

In one aspect of this embodiment, the bioactive agent is an immunemodulator, including but not limited to a checkpoint inhibitor,including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor,PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor,V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, smallmolecule, peptide, nucleotide, or other inhibitor. In certain aspects,the immune modulator is an antibody, such as a monoclonal antibody.

PD-1 inhibitors that blocks the interaction of PD-1 and PD-L1 by bindingto the PD-1 receptor, and in turn inhibit immune suppression include,for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab,AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680(AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1(Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042(Tesaro), and the PD-L1/VISTA inhibitor CA-170 (Curis Inc.). PD-L1inhibitors that block the interaction of PD-1 and PD-L1 by binding tothe PD-L1 receptor, and in turn inhibits immune suppression, include forexample, atezolizumab (Tecentriq), durvalumab (AstraZeneca andMedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb).CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immunesuppression include, but are not limited to, ipilimumab, tremelimumab(AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (Agenus). LAG-3checkpoint inhibitors, include, but are not limited to, BMS-986016(Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (PrimaBioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013(MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

In yet another embodiment, one of the active compounds described hereincan be administered in an effective amount for the treatment of abnormaltissue of the female reproductive system such as breast, ovarian,endometrial, or uterine cancer, in combination or alternation with aneffective amount of an estrogen inhibitor including but not limited to aSERM (selective estrogen receptor modulator), a SERD (selective estrogenreceptor degrader), a complete estrogen receptor degrader, or anotherform of partial or complete estrogen antagonist or agonist. Partialanti-estrogens like raloxifene and tamoxifen retain some estrogen-likeeffects, including an estrogen-like stimulation of uterine growth, andalso, in some cases, an estrogen-like action during breast cancerprogression which actually stimulates tumor growth. In contrast,fulvestrant, a complete anti-estrogen, is free of estrogen-like actionon the uterus and is effective in tamoxifen-resistant tumors.Non-limiting examples of anti-estrogen compounds are provided in WO2014/19176 assigned to Astra Zeneca, WO2013/090921, WO 2014/203129, WO2014/203132, and US2013/0178445 assigned to Olema Pharmaceuticals, andU.S. Pat. Nos. 9,078,871, 8,853,423, and 8,703, 810, as well as US2015/0005286, WO 2014/205136, and WO 2014/205138. Additionalnon-limiting examples of anti-estrogen compounds include: SERMS such asanordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphenecitrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen,toremifene, and fulvestratnt; aromatase inhibitors such asaminoglutethimide, testolactone, anastrozole, exemestane, fadrozole,formestane, and letrozole; and antigonadotropins such as leuprorelin,cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate,delmadinone acetate, dydrogesterone, medroxyprogesterone acetate,megestrol acetate, nomegestrol acetate, norethisterone acetate,progesterone, and spironolactone. Other estrogenic ligands that can beused according to the present invention are described in U.S. Pat. Nos.4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011/156518, U.S. Pat.Nos. 8,455,534 and 8,299,112, 9,078,871; 8,853,423; 8,703,810; US2015/0005286; and WO 2014/205138, US2016/0175289, US2015/0258080, WO2014/191726, WO 2012/084711; WO 2002/013802; WO 2002/004418; WO2002/003992; WO 2002/003991; WO 2002/003990; WO 2002/003989; WO2002/003988; WO 2002/003986; WO 2002/003977; WO 2002/003976; WO2002/003975; WO 2006/078834; U.S. Pat. No. 6,821,989; US 2002/0128276;U.S. Pat. No. 6,777,424; US 2002/0016340; U.S. Pat. Nos. 6,326,392;6,756,401; US 2002/0013327; U.S. Pat. Nos. 6,512,002; 6,632,834; US2001/0056099; U.S. Pat. Nos. 6,583,170; 6,479,535; WO 1999/024027; U.S.Pat. No. 6,005,102; EP 0802184; U.S. Pat. Nos. 5,998,402; 5,780,497,5,880,137, WO 2012/048058 and WO 2007/087684.

In another embodiment, an active compounds described herein can beadministered in an effective amount for the treatment of abnormal tissueof the male reproductive system such as prostate or testicular cancer,in combination or alternation with an effective amount of an androgen(such as testosterone) inhibitor including but not limited to aselective androgen receptor modulator, a selective androgen receptordegrader, a complete androgen receptor degrader, or another form ofpartial or complete androgen antagonist. In one embodiment, the prostateor testicular cancer is androgen-resistant. Non-limiting examples ofanti-androgen compounds are provided in WO 2011/156518 and U.S. Pat.Nos. 8,455,534 and 8,299,112. Additional non-limiting examples ofanti-androgen compounds include: enzalutamide, apalutamide, cyproteroneacetate, chlormadinone acetate, spironolactone, canrenone, drospirenone,ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

In one embodiment, the bioactive agent is an ALK inhibitor. Examples ofALK inhibitors include but are not limited to Crizotinib, Alectinib,ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026,PF-06463922, entrectinib (RXDX-101), and AP26113.

In one embodiment, the bioactive agent is an EGFR inhibitor. Examples ofEGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa),afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso),olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816),PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272);avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988(Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146,WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer).

In one embodiment, the bioactive agent is an HER-2 inhibitor. Examplesof HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumabemtansine, and pertuzumab.

In one embodiment, the bioactive agent is a CD20 inhibitor. Examples ofCD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab,tositumomab, and ocrelizumab.

In one embodiment, the bioactive agent is a JAK3 inhibitor. Examples ofJAK3 inhibitors include tasocitinib.

In one embodiment, the bioactive agent is a BCL-2 inhibitor. Examples ofBCL-2 inhibitors include venetoclax, ABT-199(4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide),ABT-737(4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263((R)-4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide),GX15-070 (obatoclax mesylate,(2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole;methanesulfonic acid))), 2-methoxy-antimycin A3, YC 137(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester),pogosin, ethyl2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate,Nilotinib-d3, TW-37(N-[4-[[2-(1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide),Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, orG3139 (Oblimersen).

In one embodiment, the bioactive agent is a kinase inhibitor. In oneembodiment, the kinase inhibitor is selected from a phosphoinositide3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor,or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.

Examples of PI3 kinase inhibitors include but are not limited toWortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib,Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib,GS-9820, BKM120, GDC-0032 (Taselisib)(2-[4-[2-(2-Isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide),MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; orMethyl(oxo) {[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719((2S)-N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide),GSK2126458(2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide)(omipalisib), TGX-221((+)-7-Methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one),GSK2636771(2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylicacid dihydrochloride), KIN-193((R)-2-((l-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoicacid), TGR-1202/RP5264, GS-9820((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one),GS-1101(5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one),AMG-319, GSK-2269557, SAR245409(N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4methylbenzamide), BAY80-6946(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz),AS 252424(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione),CZ 24832(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide),Buparlisib(5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine),GDC-0941(2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine),GDC-0980((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)),SF1126((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecan-18-oate),PF-05212384(N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N′-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea)(gedatolisib), LY3023414, BEZ235(2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile)(dactolisib), XL-765(N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide),and GSK1059615(5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione),PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib)), LY294002, AZD8186, PF-4989216,pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173,VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75,PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib,IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424,AS-604850, apitolisib (GDC-0980; RG7422), and the structure described inWO2014/071109 having the formula:

Examples of BTK inhibitors include ibrutinib (also known asPCI-32765)(Imbruvica™)1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one),dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292(N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide)(Avila Therapeutics) (see US Patent Publication No 2011/0117073,incorporated herein in its entirety), Dasatinib([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide],LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-ibromophenyl)propenamide), GDC-0834([R—N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide],CGI-5604-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide,CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide),CNX-774(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide),CTA056(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one),GDC-0834((R)—N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide),GDC-0837((R)—N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide),HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamidehydrochloride), QL-47(1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one),and RN486(6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one),and other molecules capable of inhibiting BTK activity, for examplethose BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology& Oncology, 2013, 6:59, the entirety of which is incorporated herein byreference.

Syk inhibitors include, for example, Cerdulatinib(4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide),entospletinib(6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine),fostamatinib([6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyldihydrogen phosphate), fostamatinib disodium salt (sodium(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methylphosphate), BAY 61-3606(2-(7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamideHCl), RO9021(6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylicacid amide), imatinib (Gleevac;4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide),staurosporine, GSK143(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide),PP2(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine),PRT-060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide),PRT-062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamidehydrochloride), R112(3,3′-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348(3-Ethyl-4-methylpyridine), R406(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one),piceatannol (3-Hydroxyresveratol), YM193306(see Singh et al. Discoveryand Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (seeSingh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), Compound D (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), PRT060318 (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), luteolin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), apigenin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), quercetin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), fisetin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), myricetin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), morin (see Singh et al.Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J.Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein).

In one embodiment, the bioactive agent is a MEK inhibitor. MEKinhibitors are well known, and include, for example,trametinib/GSK1120212(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-(2H-yl}phenyl)acetamide),selumetinib(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),pimasertib/AS703026/MSC 1935369((S)—N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide),XL-518/GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol),refametinib/BAY869766/RDEAl 19(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide),PD-0325901(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide),TAK733((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione),MEK162/ARRY438162(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide),R05126766(3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one),WX-554, R04987655/CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide),or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide),U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib,PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088.

In one embodiment, the bioactive agent is a Raf inhibitor. Rafinhibitors are known and include, for example, Vemurafinib(N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide),sorafenib tosylate(4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide;4-methylbenzenesulfonate), AZ628(3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide),NVP-BHG712(4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide),RAF-265(1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine),2-Bromoaldisine(2-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf KinaseInhibitor IV(2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol),Sorafenib N-Oxide(4-[4-[[[[4-Chloro-3(trifluoroMethyl)phenyl]aMino]carbonyl]aMino]phenoxy]-N-Methyl-2pyridinecarboxaMide1-Oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628,SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818(Encorafenib).

In one embodiment, the bioactive agent is an AKT inhibitor, includingbut not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401),GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine,a FLT-3 inhibitor, including but not limited to, P406, Dovitinib,Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518),ENMD-2076, and KW-2449, or a combination thereof.

In one embodiment, the bioactive agent is an mTOR inhibitor. Examples ofmTOR inhibitors include but are not limited to rapamycin and itsanalogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus,and deforolimus. Examples of MEK inhibitors include but are not limitedto tametinib/GSK1120212(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-(2H-yl}phenyl)acetamide), selumetinob(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),pimasertib/AS703026/MSC 1935369((S)—N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide),XL-518/GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol)(cobimetinib), refametinib/BAY869766/RDEAl19(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide),PD-0325901(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide),TAK733((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione),MEK162/ARRY438162(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6carboxamide), R05126766(3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one),WX-554, R04987655/CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide), or AZD8330(2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

In one embodiment, the bioactive agent is a RAS inhibitor. Examples ofRAS inhibitors include but are not limited to Reolysin and siG12D LODER.

In one embodiment, the bioactive agent is a HSP inhibitor. HSPinhibitors include but are not limited to Geldanamycin or17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol.

Additional bioactive compounds include, for example, everolimus,trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693,RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258,GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054,PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, anaurora kinase inhibitor, a PIK-1 modulator, an HDAC inhbitor, a c-METinhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, ananti-HGF antibody, a focal adhesion kinase inhibitor, a Map kinasekinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, panitumumab,amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin,ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan,tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111,131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan,IL13-PE38QQR, INO 1001, IPdR₁ KRX-0402, lucanthone, LY317615, neuradiab,vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin,ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide,gemcitabine, doxorubicin, liposomal doxorubicin,5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole,DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib,AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelinpamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate,megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide,megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib,canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016,Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SUl1248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide,L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil,cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine,dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-freepaclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa, darbepoetin alfa and mixtures thereof.

In one embodiment, the bioactive agent is selected from, but are notlimited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®),Nilotinib (Tasigna®), Bosutinib (Bosulif)), Trastuzumab (Herceptin®),trastuzumab-DM1, Pertuzumab (Perjeta™), Lapatinib (Tykerb®), Gefitinib(Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab(Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat(Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin(Panretin®), Tretinoin (Vesanoid®), Carfilizomib (Kyprolis™),Pralatrexate (Folotyn®), Bevacizumab (Avastin®), Ziv-aflibercept(Zaltrap®), Sorafenib (Nexavar®, Sunitinib (Sutent®), Pazopanib(Votrient®), Regorafenib (Stivarga®), and Cabozantinib (Cometriq™).

In certain aspects, the bioactive agent is an anti-inflammatory agent, achemotherapeutic agent, a radiotherapeutic, an additional therapeuticagent, or an immunosuppressive agent.

Suitable chemotherapeutic bioactive agents include, but are not limitedto, a radioactive molecule, a toxin, also referred to as cytotoxin orcytotoxic agent, which includes any agent that is detrimental to theviability of cells, and liposomes or other vesicles containingchemotherapeutic compounds. General anticancer pharmaceutical agentsinclude: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®),Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®),Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase(Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide(VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®),Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone(Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib(Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples ofadditional suitable chemotherapeutic agents include but are not limitedto 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine,6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylatingagent, allopurinol sodium, altretamine, amifostine, anastrozole,anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum(II) (DDP) cisplatin), diamino dichloro platinum, anthracycline, anantibiotic, an antimetabolite, asparaginase, BCG live (intravesical),betamethasone sodium phosphate and betamethasone acetate, bicalutamide,bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin,capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU),Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens,Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasinB, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerlyactinomycin), daunirubicin HCL, daunorucbicin citrate, denileukindiftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione,Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coliL-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterifiedestrogens, estradiol, estramustine phosphate sodium, ethidium bromide,ethinyl estradiol, etidronate, etoposide citrororum factor, etoposidephosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate,fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids,goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea,idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole,leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine,lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesteroneacetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna,methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane,mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL,paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL,plimycin, polifeprosan 20 with carmustine implant, porfimer sodium,procaine, procarbazine HCL, propranolol, rituximab, sargramostim,streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone,tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL,toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastinesulfate, vincristine sulfate, and vinorelbine tartrate.

Additional therapeutic agents that can be administered in combinationwith a degronimer disclosed herein can include bevacizumab, sutinib,sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib,vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522),cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab,dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine,atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab,dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib,carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir,nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat,mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin,talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib,dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib,bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991,ribociclib (LEEO11), amebaciclib (LY2835219), HDM201, fulvestrant(Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398,necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

In one aspect of the invention, the disclosed compound is administeredin combination with an anti-infective agent, for example but not limitedto an anti-HIV agent, anti-HCV agent, anti-HBV agent, or otheranti-viral or anti-bacterial agent. In one embodiment, the anti-HIVagent can be, but is not limited to, for example, a nucleoside reversetranscriptase inhibitor (NRTI), other non-nucloeoside reversetranscriptase inhibitor, protease inhibitor, fusion inhibitor, amongothers. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)include, but are not limited to, Abacavir or ABC (Ziagen), Didanosine orddl (Videx), Emtricitabine or FTC (Emtriva), Lamivudine or 3TC (Epivir),ddC (zalcitabine), Stavudine or d4T (Zerit), Tenofovircor TDF (Viread),D-D4FC (Reverset), and Zidovudine or AZT or ZDV (Retrovir).Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) include, butare not limited to, Delavirdine (Rescriptor), Efavirenz (Sustiva),Etravirine (Intelence), Nevirapine (Viramune), and Rilpivirine(Edurant). Anti-HIV Protease Inhibitors (PIs) include, but are notlimited to, Atazanavir or ATV (Reyataz), Darunavir or DRV (Prezista),Fosamprenavir or FPV (Lexiva), Indinavir or IDV (Crixivan),Lopinavir+ritonavir, or LPV/r (Kaletra), Nelfinavir or NFV (Viracept),Ritonavir or RTV (Norvir), Saquinavir or SQV (Invirase), Tipranavir, orTPV (Aptivus), Cobicistat (Tybost), Atazanavir+cobicistat, or ATV/COBI(Evotaz), Darunavir+cobicistat, or DRV/COBI (Prezcobix). Anti-HIV FusionInhibitors include, but are not limited to, Enfuvirtide or ENF or T-20(Fuzeon). Anti-HIV also include, but are not limited to, Maraviroc orMVC (Selzentry). Anti-HIV Integrase Inhibitors include, but are notlimited to Dolutegravir (Tivicay), Elvitegravir (Vitekta), Raltegravir(Isentress). Anti-HIV combinations agents includeAbacavir+Dolutegravir+lamivudine, or ABC/DTG/3TC (Triumeq),Abacavir+lamivudine or ABC/3TC (Epzicom),Abacavir+lamivudine+zidovudine, or ABC/3TC/ZDV (Trizivir),Efavirenz+emtricitabine+tenofovir or EFV/FTC/TDF (Atripla, Tribuss),elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide orEVG/COBI/FTC/TAF or ECF/TAF (Genvoya; (Stribild),emtricitabine+rilpivirine+tenofovir or FTC/RPV/TAF (Odefsey);Emtricitabine+rilpivirine+tenofovir or FTC/RPV/TDF (Complera),Emtricitabine+tenofovir or TAF/FTC (Descovy), emtricitabine andtenofovir disoproxil fumarate (Truvada), and Lamivudine+zidovudine or3TC/ZDV (Combivir). Other anti-HIV compounds include, but are notlimited to Racivir, L-FddC, L-FD4C, SQVM (Saquinavir mesylate), IDV(Indinavir), SQV (Saquinavir), APV (Amprenavir), LPV (Lopinavir), fusioninhibitors such as T20, among others, fuseon and mixtures thereof,including anti-HIV compounds presently in clinical trials or indevelopment.

Other anti-HIV agents which may be used in co-administration with thedisclosed compounds according to the present invention. NNRTIs may beselected from the group consisting of nevirapine (BI-R6-587),delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781(N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2methyl3-furancarbothiamide),etravirine (TMC125), Trovirdine (Ly300046.HCl), HI-236, HI-240, HI-280,HI-281, rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, Baicalin(TJN-151) ADAM-II (Methyl3′,3′-dichloro-4′,4″-dimethoxy-5′,5″-bis(methoxycarbonyl)-6,6-diphenylhexenoate),Methyl3-Bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoate(Alkenyldiarylmethane analog, Adam analog),(5-chloro-3-(phenylsulfinyl)-2′-indolecarboxamide), AAP-BHAP (U-104489or PNU-104489), Capravirine (AG-1549, S-1153), atevirdine (U-87201E),aurin tricarboxylic acid (SD-095345),1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[3-(Ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine,1-[(6-Formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[[5-(Methylsulfonyloxy)-2-indoyly)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,U88204E, Bis(2-nitrophenyl)sulfone (NSC 633001), Calanolide A(NSC675451), Calanolide B,6-Benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961,E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (Foscavir), HEPT(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M(1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine),HEPT-S(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine),Inophyllum P, L-737,126, Michellamine A (NSC650898), Michellamine B(NSC649324), Michellamine F,6-(3,5-Dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil,6-(3,5-Dimethylbenzyl)-1-(ethyoxymethyl)-5-isopropyluracil, NPPS, E-BPTU(NSC 648400), Oltipraz(4-Methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione),N-{2-(2-Chloro-6-fluorophenethyl]-N′-(2-thiazolyl)thiourea (PETT Cl, Fderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-bromopyridyl)]thiourea {PETTderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-methylpyridyl]thiourea {PETTPyridyl derivative),N-[2-(3-Fluorofuranyl)ethyl]-N′-[2-(5-chloropyridyl)]thiourea,N-[2-(2-Fluoro-6-ethoxyphenethyl)]-N′-[2-(5-bromopyridyl)]thiourea,N-(2-Phenethyl)-N′-(2-thiazolyl)thiourea (LY-73497), L-697,639,L-697,593, L-697,661,342-(4,7-Difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pypridin-2(1H)-thione(2-Pyridinone Derivative),3-[[(2-Methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pypridin-2(1H)-thione,R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720,Suramin Sodium, TBZ (Thiazolobenzimidazole, NSC 625487),Thiazoloisoindol-5-one,(+)(R)-9b-(3,5-Dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one, Tivirapine (R86183), UC-38 and UC-84, among others.

In one aspect of the invention, the disclosed compound when used totreat an HCV infection can be administered in combination with anotheranti-HCV agent. Anti-HCV agents are known in the art. To date, a numberof fixed dose drug combinations have been approved for the treatment ofHCV. Harvoni® (Gilead Sciences, Inc.) contains the NS5A inhibitorledipasvir and the NS5B inhibitor sofosbuvir. Technivie™ (AbbVie, Inc.)is a fixed-dose combination containing ombitasvir, an NS5A inhibitor;paritaprevir, an NS3/4A protease inhibitor; and ritonavir, a CYP3Ainhibitor. Daklinza™ (daclatasvir, Bristol-Myers Squibb) is a HCV NS5Ainhibitor indicated for use with sofosbuvir for the treatment of chronicgenotype 3 infection. Zepatier™ (Merck & Co.) has recently been approvedfor the treatment of chronic HCV genotypes 1 and 4. Zepatier™ is afixed-dose combination product containing elbasvir, an HCV NS5Ainhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor. Zepatier™is indicated with or without ribavirin. Epclusa® (Gilead Sciences, Inc.)is a fixed-dose combination tablet containing sofosbuvir andvelpatasvir.

Additional anti-HCV agents and combinations thereof include thosedescribed in U.S. Pat. Nos. 9,382,218; 9,321,753; 9,249,176; 9,233,974;9,221,833; 9,211,315; 9,194,873; 9,186,369; 9,180,193; 9,156,823;9,138,442; 9,133,170; 9,108,999; 9,090,559; 9,079,887; 9,073,943;9,073,942; 9,056,090; 9,051,340; 9,034,863; 9,029,413; 9,011,938;8,987,302; 8,945,584; 8,940,718; 8,927,484; 8,921,341; 8,884,030;8,841,278; 8,822,430; 8,772,022; 8,765,722; 8,742,101; 8,741,946;8,674,085; 8,673,288; 8,669,234; 8,663,648; 8,618,275; 8,580,252;8,575,195; 8,575,135; 8,575,118; 8,569,302; 8,524,764; 8,513,298;8,501,714; 8,404,651; 8,273,341; 8,257,699; 8,197,861; 8,158,677;8,105,586; 8,093,353; 8,088,368; 7,897,565; 7,871,607; 7,846,431;7,829,081; 7,829,077; 7,824,851; 7,572,621; and 7,326,536; Patentsassigned to Alios: U.S. Pat. Nos. 9,365,605; 9,346,848; 9,328,119;9,278,990; 9,249,174; 9,243,022; 9,073,960; 9,012,427; 8,980,865;8,895,723; 8,877,731; 8,871,737; 8,846,896 and 8,772,474; Achillion U.S.Pat. Nos. 9,273,082; 9,233,136; 9,227,952; 9,133,115; 9,125,904;9,115,175; 9,085,607; 9,006,423; 8,946,422; 8,835,456; 8,809,313;8,785,378; 8,614,180; 8,445,430; 8,435,984; 8,183,263; 8,173,636;8,163,693; 8,138,346; 8,114,888; 8,106,209; 8,088,806; 8,044,204;7,985,541; 7,906,619; 7,902,365; 7,767,706; 7,741,334; 7,718,671;7,659,399; 7,476,686; 7,439,374; 7,365,068; 7,199,128; and 7,094,807;Cocrystal Pharma Inc. U.S. Pat. Nos. 9,181,227; 9,173,893; 9,040,479 and8,771,665; Gilead Sciences U.S. Pat. Nos. 9,353,423; 9,346,841;9,321,800; 9,296,782; 9,296,777; 9,284,342; 9,238,039; 9,216,996;9,206,217; 9,161,934; 9,145,441; 9,139,604; 9,090,653; 9,090,642;9,085,573; 9,062,092; 9,056,860; 9,045,520; 9,045,462; 9,029,534;8,980,878; 8,969,588; 8,962,652; 8,957,046; 8,957,045; 8,946,238;8,933,015; 8,927,741; 8,906,880; 8,889,159; 8,871,785; 8,841,275;8,815,858; 8,809,330; 8,809,267; 8,809,266; 8,779,141; 8,765,710;8,759,544; 8,759,510; 8,735,569; 8,735,372; 8,729,089; 8,722,677;8,716,264; 8,716,263; 8,716,262; 8,697,861; 8,664,386; 8,642,756;8,637,531; 8,633,309; 8,629,263; 8,618,076; 8,592,397; 8,580,765;8,569,478; 8,563,530; 8,551,973; 8,536,187; 8,513,186; 8,513,184;8,492,539; 8,486,938; 8,481,713; 8,476,225; 8,420,597; 8,415,322;8,338,435; 8,334,270; 8,329,926; 8,329,727; 8,324,179; 8,283,442;8,263,612; 8,232,278; 8,178,491; 8,173,621; 8,163,718; 8,143,394;patents assigned to Idenix, acquired by Merck, include U.S. Pat. Nos.9,353,100; 9,309,275; 9,296,778; 9,284,307; 9,249,173; 9,243,025;9,211,300; 9,187,515; 9,187,496, 9,109,001; 8,993,595; 8,951,985;8,691,788; 8,680,071; 8,637,475; 8,507,460; 8,377,962; 8,362,068;8,343,937; 8,299,038; 8,193, 372; 8,093,379; 7,951,789; 7,932,240;7,902,202; 7,662,798; 7,635,689; 7,625,875; 7,608,600; 7,608,597;7,582,618; 7,547,704; 7,456,155; 7,384,924; 7,365,057; 7,192,936;7,169,766; 7,163,929; 7,157,441; 7,148,206; 7,138,376; 7,105,493;6,914,054 and 6,812,219; patents assigned to Merck include U.S. Pat.Nos. 9,364,482; 9,339,541; 9,328,138; 9,265,773; 9,254,292; 9,243,002;9,242,998; 9,242,988; 9,242,917; 9,238,604; 9,156,872; 9,150,603;9,139,569; 9,120,818; 9,090,661; 9,073,825; 9,061,041; 8,987,195;8,980,920; 8,927,569; 8,871,759; 8,828,930; 8,772,505; 8,715,638;8,697,694; 8,637,449; 8,609,635; 8,557,848; 8,546,420; 8,541,434;8,481,712; 8,470,834; 8,461,107; 8,404,845; 8,377,874; 8,377,873;8,354,518; 8,309,540; 8,278,322; 8,216,999; 8,148,349; 8,138,164;8,080,654; 8,071,568; 7,973,040; 7,935,812; 7,915,400; 7,879,815;7,879,797; 7,632,821; 7,569,374; 7,534,767; 7,470,664 and 7,329,732;patent application publication US 2013/0029904 to Boehringer IngelheimGMBH and US 2014/0113958 to Stella Aps.

In one embodiment, the additional therapy is a monoclonal antibody(MAb). Some MAbs stimulate an immune response that destroys cancercells. Similar to the antibodies produced naturally by B cells, theseMAbs may “coat” the cancer cell surface, triggering its destruction bythe immune system. For example, bevacizumab targets vascular endothelialgrowth factor (VEGF), a protein secreted by tumor cells and other cellsin the tumor's microenvironment that promotes the development of tumorblood vessels. When bound to bevacizumab, VEGF cannot interact with itscellular receptor, preventing the signaling that leads to the growth ofnew blood vessels. Similarly, cetuximab and panitumumab target theepidermal growth factor receptor (EGFR), and trastuzumab targets thehuman epidermal growth factor receptor 2 (HER-2). MAbs that bind to cellsurface growth factor receptors prevent the targeted receptors fromsending their normal growth-promoting signals. They may also triggerapoptosis and activate the immune system to destroy tumor cells.

In one aspect of the present invention, the bioactive agent is animmunosuppressive agent. The immunosuppressive agent can be acalcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g.Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTORinhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus(RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus,biolimus-7, biolimus-9, a rapalog, e.g. ridaforolimus, azathioprine,campath 1H, a S1P receptor modulator, e.g. fingolimod or an analoguethereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof,e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil(CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®,THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1,15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig,anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®),mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981(pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g,etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®),infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®),Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab,Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate,benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin,aspirin and ibuprofen.

V. Pharmaceutical Compositions

The compounds of Formula I, II, III, VI, V, VI or VII, as disclosedherein can be administered as the neat chemical, but are more typicallyadministered as a pharmaceutical composition, that includes an effectiveamount for a host, typically a human, in need of such treatment for anyof the disorders described herein. Accordingly, the disclosure providespharmaceutical compositions comprising an effective amount of thedisclosed compound or pharmaceutically acceptable salt thereof togetherwith at least one pharmaceutically acceptable carrier for any of theuses described herein. The pharmaceutical composition may contain thedisclosed compound or salt as the only active agent, or, in analternative embodiment, the disclosed compound and at least oneadditional active agent.

Compounds disclosed herein may be administered by any suitable routedesired by the healthcare provider, including orally, topically,systemically, parenterally, by inhalation or spray, sublingually, viaimplant, including ocular implant, transdermally, via buccaladministration, rectally, as an ophthalmic solution, injection,including ocular injection, intraveneous, intra-arterial, intra-aortal,intracranial, subdermal, intraperitioneal, subcutaneous, transnasal,sublingual, or rectal or by other means, in dosage unit formulationscontaining conventional pharmaceutically acceptable carriers.

In general, the compositions of the disclosure will be administered in atherapeutically effective amount by the desired mode of administration.Suitable dosage ranges depend upon numerous factors such as the severityof the disease to be treated, the age and relative health of thesubject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this application, to ascertaina therapeutically effective amount of the compositions of the disclosurefor a given disease.

In certain embodiments the pharmaceutical composition is in a dosageform that contains from about 0.1 mg to about 2000 mg, from about 10,25, 50 or 100 mg to about 1000 mg, from about 100 mg to about 800 mg, orfrom about 50 to 500, 75 to 500, or 200 mg to about 600 mg of the activecompounds and optionally for example from about 0.1 mg to about 2000 mg,from about 10, 25, 50 or 100 mg to about 1000 mg, from about 50 to 500,75 to 500, from about 100 mg to about 800 mg, or from about 200 mg toabout 600 mg of an additional active agent in a unit dosage form.Examples are dosage forms with at least 0.1, 1, 5, 10, 25, 50, 100, 200,250, 300, 400, 500, 600, 700, 750 or 800 mg of active compound, or itssalt.

The therapeutically effective dosage of any active compound describedherein will be determined by the health care practitioner depending onthe condition, size and age of the patient as well as the route ofdelivery. In one non-limited embodiment, a dosage from about 0.1 toabout 200 mg/kg, from about 0.01 mg/kg to about 250 mg/kg body weight,more preferably about 0.1 mg/kg to up to about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 20 or 30 mg/kg, in at least one dose. In some embodiments, thedosage may be the amount of compound needed to provide a serumconcentration of the active compound of up to about 10 nM, 50 nM, 100nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1μM, 5 μM, 10 μM, 20 μM, 30 μM, or 40 μM.

The pharmaceutical composition may be formulated as any pharmaceuticallyuseful form, e.g., as an aerosol, a cream, a gel, a pill, an injectionor infusion solution, a capsule, a tablet, a syrup, a transdermal patch,a subcutaneous patch, a dry powder, an inhalation formulation, in amedical device, suppository, buccal, or sublingual formulation,parenteral formulation, or an ophthalmic solution. Some dosage forms,such as tablets and capsules, are subdivided into suitably sized unitdoses containing appropriate quantities of the active components, e.g.,an effective amount to achieve the desired purpose.

“Pharmaceutically acceptable carriers” for therapeutic use are wellknown in the pharmaceutical art, and are described, for example, inRemington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.: MackPublishing Company, 1990). For example, sterile saline andphosphate-buffered saline at physiological pH can be used.Preservatives, stabilizers, dyes and even flavoring agents can beprovided in the pharmaceutical composition. For example, sodiumbenzoate, sorbic acid and esters of p-hydroxybenzoic acid can be addedas preservatives. Id. at 1449. In addition, antioxidants and suspendingagents can be used. Id. Carriers include excipients must be ofsufficiently high purity and sufficiently low toxicity to render themsuitable for administration to the patient being treated. The carriercan be inert or it can possess pharmaceutical benefits of its own. Theamount of carrier employed in conjunction with the disclosed compound issufficient to provide a practical quantity of material foradministration per unit dose of the compound, as described in moredetail herein.

Classes of carriers include, but are not limited to binders, bufferingagents, coloring agents, diluents, disintegrants, emulsifiers,flavorants, glidents, lubricants, preservatives, stabilizers,surfactants, tableting agents, and wetting agents. Some carriers may belisted in more than one class, for example vegetable oil may be used asa lubricant in some formulations and a diluent in others. Exemplarypharmaceutically acceptable carriers include sugars, starches,celluloses, powdered tragacanth, malt, gelatin; talc, and vegetableoils. Optional active agents may be included in a pharmaceuticalcomposition, which do not substantially interfere with the activity ofthe disclosed compounds of the present invention.

Additionally, auxiliary substances, such as wetting or emulsifyingagents, biological buffering substances, surfactants, and the like, canbe present in such vehicles. A biological buffer can be any solutionwhich is pharmacologically acceptable and which provides the formulationwith the desired pH, i.e., a pH in the physiologically acceptable range.Examples of buffer solutions include saline, phosphate buffered saline,Tris buffered saline, Hank's buffered saline, and the like.

Depending on the intended mode of administration, the pharmaceuticalcompositions can be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, creams, ointments, lotions or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include an effective amount of theselected drug in combination with a pharmaceutically acceptable carrierand, in addition, can include other pharmaceutical agents, adjuvants,diluents, buffers, and the like.

Thus, the compositions of the disclosure can be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal orparenteral (including intramuscular, intra-arterial, intrathecal,subcutaneous and intravenous) administration or in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is intravenous or oral using a convenient daily dosageregimen which can be adjusted according to the degree of affliction.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmaceutically administrablecompositions can, for example, be prepared by dissolving, dispersing,and the like, an active compound as described herein and optionalpharmaceutical adjuvants in an excipient, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered can also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate, andthe like. Actual methods of preparing such dosage forms are known, orwill be apparent, to those skilled in this art; for example, seeRemington's Pharmaceutical Sciences, referenced above.

In yet another embodiment is the use of permeation enhancer excipientsincluding polymers such as: polycations (chitosan and its quaternaryammonium derivatives, poly-L-arginine, aminated gelatin); polyanions(N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers(carboxymethyl cellulose-cysteine, polycarbophil-cysteine,chitosan-thiobutylamidine, chitosan-thioglycolic acid,chitosan-glutathione conjugates).

For oral administration, the composition will generally take the form ofa tablet, capsule, a softgel capsule or can be an aqueous or nonaqueoussolution, suspension or syrup. Tablets and capsules are preferred oraladministration forms. Tablets and capsules for oral use can include oneor more commonly used carriers such as lactose and corn starch.Lubricating agents, such as magnesium stearate, are also typicallyadded. Typically, the compositions of the disclosure can be combinedwith an oral, non-toxic, pharmaceutically acceptable, inert carrier suchas lactose, starch, sucrose, glucose, methyl cellulose, magnesiumstearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol andthe like. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Suitable binders include starch, gelatin,natural sugars such as glucose or beta-lactose, corn sweeteners, naturaland synthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

When liquid suspensions are used, the active agent can be combined withany oral, non-toxic, pharmaceutically acceptable inert carrier such asethanol, glycerol, water, and the like and with emulsifying andsuspending agents. If desired, flavoring, coloring and/or sweeteningagents can be added as well. Other optional components for incorporationinto an oral formulation herein include, but are not limited to,preservatives, suspending agents, thickening agents, and the like.

Parenteral formulations can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solubilizationor suspension in liquid prior to injection, or as emulsions. Preferably,sterile injectable suspensions are formulated according to techniquesknown in the art using suitable carriers, dispersing or wetting agentsand suspending agents. The sterile injectable formulation can also be asterile injectable solution or a suspension in a nontoxic parenterallyacceptable diluent or solvent. Among the acceptable vehicles andsolvents that can be employed are water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile, fixed oils, fatty estersor polyols are conventionally employed as solvents or suspending media.In addition, parenteral administration can involve the use of a slowrelease or sustained release system such that a constant level of dosageis maintained.

Parenteral administration includes intraarticular, intravenous,intramuscular, intradermal, intraperitoneal, and subcutaneous routes,and include aqueous and non-aqueous, isotonic sterile injectionsolutions, which can contain antioxidants, buffers, bacteriostats, andsolutes that render the formulation isotonic with the blood of theintended recipient, and aqueous and non-aqueous sterile suspensions thatcan include suspending agents, solubilizers, thickening agents,stabilizers, and preservatives. Administration via certain parenteralroutes can involve introducing the formulations of the disclosure intothe body of a patient through a needle or a catheter, propelled by asterile syringe or some other mechanical device such as an continuousinfusion system. A formulation provided by the disclosure can beadministered using a syringe, injector, pump, or any other devicerecognized in the art for parenteral administration.

Preferably, sterile injectable suspensions are formulated according totechniques known in the art using suitable carriers, dispersing orwetting agents and suspending agents. The sterile injectable formulationcan also be a sterile injectable solution or a suspension in a nontoxicparenterally acceptable diluent or solvent. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oils,fatty esters or polyols are conventionally employed as solvents orsuspending media. In addition, parenteral administration can involve theuse of a slow release or sustained release system such that a constantlevel of dosage is maintained.

Preparations according to the disclosure for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms can also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They can be sterilized by, forexample, filtration through a bacteria retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured using sterile water, or some other sterile injectablemedium, immediately before use.

Sterile injectable solutions are prepared by incorporating one or moreof the compounds of the disclosure in the required amount in theappropriate solvent with various of the other ingredients enumeratedabove, as required, followed by filtered sterilization. Generally,dispersions are prepared by incorporating the various sterilized activeingredients into a sterile vehicle which contains the basic dispersionmedium and the required other ingredients from those enumerated above.In the case of sterile powders for the preparation of sterile injectablesolutions, the preferred methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof. Thus, for example, a parenteralcomposition suitable for administration by injection is prepared bystirring 1.5% by weight of active ingredient in 10% by volume propyleneglycol and water. The solution is made isotonic with sodium chloride andsterilized.

Formulations suitable for rectal administration are typically presentedas unit dose suppositories. These may be prepared by admixing the activedisclosed compound with one or more conventional solid carriers, forexample, cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferablytake the form of an ointment, cream, lotion, paste, gel, spray, aerosol,or oil. Carriers which may be used include petroleum jelly, lanoline,polyethylene glycols, alcohols, transdermal enhancers, and combinationsof two or more thereof.

Formulations suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Formulationssuitable for transdermal administration may also be delivered byiontophoresis (see, for example, Pharmaceutical Research 3 (6):318(1986)) and typically take the form of an optionally buffered aqueoussolution of the active compound. In one embodiment, microneedle patchesor devices are provided for delivery of drugs across or into biologicaltissue, particularly the skin. The microneedle patches or devices permitdrug delivery at clinically relevant rates across or into skin or othertissue barriers, with minimal or no damage, pain, or irritation to thetissue.

Formulations suitable for administration to the lungs can be deliveredby a wide range of passive breath driven and active power drivensingle/-multiple dose dry powder inhalers (DPI). The devices mostcommonly used for respiratory delivery include nebulizers, metered-doseinhalers, and dry powder inhalers. Several types of nebulizers areavailable, including jet nebulizers, ultrasonic nebulizers, andvibrating mesh nebulizers. Selection of a suitable lung delivery devicedepends on parameters, such as nature of the drug and its formulation,the site of action, and pathophysiology of the lung.

Additional non-limiting examples of drug delivery devices and methodsinclude, for example, US20090203709 titled “Pharmaceutical Dosage FormFor Oral Administration Of Tyrosine Kinase Inhibitor” (AbbottLaboratories); US20050009910 titled “Delivery of an active drug to theposterior part of the eye via subconjunctival or periocular delivery ofa prodrug”, US 20130071349 titled “Biodegradable polymers for loweringintraocular pressure”, U.S. Pat. No. 8,481,069 titled “Tyrosine kinasemicrospheres”, U.S. Pat. No. 8,465,778 titled “Method of making tyrosinekinase microspheres”, U.S. Pat. No. 8,409,607 titled “Sustained releaseintraocular implants containing tyrosine kinase inhibitors and relatedmethods”, U.S. Pat. No. 8,512,738 and US 2014/0031408 titled“Biodegradable intravitreal tyrosine kinase implants”, US 2014/0294986titled “Microsphere Drug Delivery System for Sustained IntraocularRelease”, U.S. Pat. No. 8,911,768 titled “Methods For TreatingRetinopathy With Extended Therapeutic Effect” (Allergan, Inc.); U.S.Pat. No. 6,495,164 titled “Preparation of injectable suspensions havingimproved injectability” (Alkermes Controlled Therapeutics, Inc.); WO2014/047439 titled “Biodegradable Microcapsules Containing FillingMaterial” (Akina, Inc.); WO 2010/132664 titled “Compositions And MethodsFor Drug Delivery” (Baxter International Inc. Baxter Healthcare SA);US20120052041 titled “Polymeric nanoparticles with enhanced drug loadingand methods of use thereof” (The Brigham and Women's Hospital, Inc.);US20140178475, US20140248358, and US20140249158 titled “TherapeuticNanoparticles Comprising a Therapeutic Agent and Methods of Making andUsing Same” (BIND Therapeutics, Inc.); U.S. Pat. No. 5,869,103 titled“Polymer microparticles for drug delivery” (Danbiosyst UK Ltd.); U.S.Pat. No. 8,628,801 titled “Pegylated Nanoparticles” (Universidad deNavarra); US2014/0107025 titled “Ocular drug delivery system” (JadeTherapeutics, LLC); U.S. Pat. No. 6,287,588 titled “Agent deliveringsystem comprised of microparticle and biodegradable gel with an improvedreleasing profile and methods of use thereof”, U.S. Pat. No. 6,589,549titled “Bioactive agent delivering system comprised of microparticleswithin a biodegradable to improve release profiles” (Macromed, Inc.);U.S. Pat. Nos. 6,007,845 and 5,578,325 titled “Nanoparticles andmicroparticles of non-linear hydrophilic hydrophobic multiblockcopolymers” (Massachusetts Institute of Technology); US20040234611,US20080305172, US20120269894, and US20130122064 titled “Ophthalmic depotformulations for periocular or subconjunctival administration (NovartisAg); U.S. Pat. No. 6,413,539 titled “Block polymer” (Poly-Med, Inc.); US20070071756 titled “Delivery of an agent to ameliorate inflammation”(Peyman); US 20080166411 titled “Injectable Depot Formulations AndMethods For Providing Sustained Release Of Poorly Soluble DrugsComprising Nanoparticles” (Pfizer, Inc.); U.S. Pat. No. 6,706,289 titled“Methods and compositions for enhanced delivery of bioactive molecules”(PR Pharmaceuticals, Inc.); and U.S. Pat. No. 8,663,674 titled“Microparticle containing matrices for drug delivery” (Surmodics).

VI. General Synthesis

The compounds described herein can be prepared by methods known by thoseskilled in the art. In one non-limiting example the disclosed compoundscan be using the schemes.

Compounds of the present invention with stereocenters may be drawnwithout steroechemistry for convenience. One skilled in the art willrecognize that pure enantiomers and diastereomers can be prepared bymethods known in the art. Examples of methods to obtain optically activematerials include at least the following.

i) physical separation of crystals—a technique whereby macroscopiccrystals of the individual enantiomers are manually separated. Thistechnique can be used if crystals of the separate enantiomers exist,i.e., the material is a conglomerate, and the crystals are visuallydistinct;

ii) simultaneous crystallization—a technique whereby the individualenantiomers are separately crystallized from a solution of the racemate,possible only if the latter is a conglomerate in the solid state;

iii) enzymatic resolutions—a technique whereby partial or completeseparation of a racemate by virtue of differing rates of reaction forthe enantiomers with an enzyme;

iv) enzymatic asymmetric synthesis—a synthetic technique whereby atleast one step of the synthesis uses an enzymatic reaction to obtain anenantiomerically pure or enriched synthetic precursor of the desiredenantiomer;

v) chemical asymmetric synthesis—a synthetic technique whereby thedesired enantiomer is synthesized from an achiral precursor underconditions that produce asymmetry (i.e., chirality) in the product,which may be achieved using chiral catalysts or chiral auxiliaries;

vi) diastereomer separations—a technique whereby a racemic compound isreacted with an enantiomerically pure reagent (the chiral auxiliary)that converts the individual enantiomers to diastereomers. The resultingdiastereomers are then separated by chromatography or crystallization byvirtue of their now more distinct structural differences and the chiralauxiliary later removed to obtain the desired enantiomer;

vii) first- and second-order asymmetric transformations—a techniquewhereby diastereomers from the racemate equilibrate to yield apreponderance in solution of the diastereomer from the desiredenantiomer or where preferential crystallization of the diastereomerfrom the desired enantiomer perturbs the equilibrium such thateventually in principle all the material is converted to the crystallinediastereomer from the desired enantiomer. The desired enantiomer is thenreleased from the diastereomer;

viii) kinetic resolutions—this technique refers to the achievement ofpartial or complete resolution of a racemate (or of a further resolutionof a partially resolved compound) by virtue of unequal reaction rates ofthe enantiomers with a chiral, non-racemic reagent or catalyst underkinetic conditions;

ix) enantiospecific synthesis from non-racemic precursors—a synthetictechnique whereby the desired enantiomer is obtained from non-chiralstarting materials and where the stereochemical integrity is not or isonly minimally compromised over the course of the synthesis;

x) chiral liquid chromatography—a technique whereby the enantiomers of aracemate are separated in a liquid mobile phase by virtue of theirdiffering interactions with a stationary phase (including via chiralHPLC). The stationary phase can be made of chiral material or the mobilephase can contain an additional chiral material to provoke the differinginteractions;

xi) chiral gas chromatography—a technique whereby the racemate isvolatilized and enantiomers are separated by virtue of their differinginteractions in the gaseous mobile phase with a column containing afixed non-racemic chiral adsorbent phase;

xii) extraction with chiral solvents—a technique whereby the enantiomersare separated by virtue of preferential dissolution of one enantiomerinto a particular chiral solvent;

xiii) transport across chiral membranes—a technique whereby a racemateis placed in contact with a thin membrane barrier. The barrier typicallyseparates two miscible fluids, one containing the racemate, and adriving force such as concentration or pressure differential causespreferential transport across the membrane barrier. Separation occurs asa result of the non-racemic chiral nature of the membrane that allowsonly one enantiomer of the racemate to pass through.

xiv) simulated moving bed chromatography, is used in one embodiment. Awide variety of chiral stationary phases are commercially available.

As shown in General Scheme 1 compounds for use in the present inventioncan be prepared by chemically combining a Degron and a Linker followedby subsequent addition of a Targeting Ligand. Similarly, in GeneralScheme 2 compounds for use in the present invention are prepared bychemically combing a Targeting Ligand and Linker first, followed bysubsequent addition of a Degron. As illustrated in the above andfollowing schemes, compounds for use in the present invention canreadily be synthesized by one skilled in the art in a variety of methodsand chemical reactions.

General Scheme 3: In Step 1, a nucleophilic Degron displaces a leavinggroup on the Linker to make a Degron Linker fragment. In Step 2, theprotecting group is removed by methods known in the art to free anucleophilic site on the Linker. In Step 3, the nucleophilic DegronLinker fragment displaces a leaving group on the Targeting Ligand toform a compound for use in the present invention. In an alternativeembodiment Step 1 and/or Step 2 is accomplished by a coupling reactioninstead of a nucleophilic attack.

General Scheme 4: In Step 1, a nucleophilic Targeting Ligand displaces aleaving group on the Linker to make a Targeting Ligand Linker fragment.In Step 2, the protecting group is removed by methods known in the artto free a nucleophilic site on the Linker. In Step 3, the nucleophilicTargeting Ligand Linker fragment displaces a leaving group on the Degronto form a compound for use in the present invention. In an alternativeembodiment Step 1 and/or Step 2 is accomplished by a coupling reactioninstead of a nucleophilic attack.

General Scheme 5 and General Scheme 6: In Step 1, a nucleophilic Linkerdisplaces a leaving group on the Degron to make a Degron Linkerfragment. In Step 2, the protecting group is removed by methods known inthe art to free a nucleophilic site on the Linker. In Step 3, thenucleophilic Degron Linker fragment displaces a leaving group on theTargeting Ligand to form a compound of Formula I or Formula II. In analternative embodiment Step 1 and/or Step 2 is accomplished by acoupling reaction instead of a nucleophilic attack.

General Scheme 7 and General Scheme 8 show a number of general reactionsfor the synthesis of functionalized degrons. Followingfunctionalization, the degron can be reacted with the linker ortargeting ligand-linker moiety. General Scheme 7 is thefunctionalization of the 1-methyl-1H indole group on the degron andGeneral Scheme 8 is the functionalization of the1-methylpyridin-2(1H)-one group on the degron.

I. Exemplary Methods for Linking Targeting Ligand and Degron Through aLinker

II. Synthesis of Representative Compounds General Schemes forGlutaramide Synthesis

Example 1: 1, 3-(4-Bromophenyl)piperidine-2,6-dione

Dimethyl 2-(4-bromophenyl)pentanedioate

Sodium hydride (1.1 equiv.) is suspended in THF and cooled to 0° C.Methyl 2-(4-bromophenyl)acetate (1 equiv.) is added dropwise and thereaction is mixed for 1 hour. Methyl 3-bromopropanoate (1 equiv.) isadded dropwise. When the reaction is judged to be complete it isquenched with aq. ammonium chloride and extracted with ethyl acetate.The combined organic layers are dried over sodium sulfate, concentratedand purified by silica gel chromatography to provide dimethyl2-(4-bromophenyl)pentanedioate. (Eur JOC, 2015, (3), 556)

3-(4-Bromophenyl)piperidine-2,6-dione

To a stirred solution of sodium amide, prepared in situ from sodiummetal and ammonia in the presence of a catalytic amount iron(III)chloride in liquid ammonia, is added a solution of the dimethyl2-(4-bromophenyl)pentanedioate in tetrahydrofuran at −33° C. Thereaction is mixed for 3 h, then excess ammonium chloride is added andthe ammonia is allowed to evaporate. Water is then added to the residueand the mixture is extracted with chloroform. The combined organic layeris dried over sodium sulfate, concentrated and purified by silica gelchromatography to provide 3-(4-bromophenyl)piperidine-2,6-dione.(Synthesis, 1985, (4), 402)

Example 2: 3-(4-Bromophenyl)piperidine-2,6-dione-3-d

tert-Butyl 3-(4-bromophenyl)-2,6-dioxopiperidine-1-carboxylate

A catalytic amount of DMAP and di-tert-butyl dicarbonate (1.05 equiv.)is added to a solution of 3-(4-bromophenyl)piperidine-2,6-dione inacetonitrile at ambient temperature. Upon the completion of the reactionthe volatiles are removed by rotary evaporation and the residue ispurified by silica gel chromatography to provide tert-butyl3-(4-bromophenyl)-2,6-dioxopiperidine-1-carboxylate.

tert-Butyl 3-(4-bromophenyl)-2,6-dioxopiperidine-1-carboxylate-3-d

A solution of tert-butyl3-(4-bromophenyl)-2,6-dioxopiperidine-1-carboxylate in anhydrous THF at−78° C. is treated with lithium bis(trimethylsilyl)amide (1.1 equiv.)for 1 hour. The reaction is quenched with deuterated acetic acid(Bioorg. Med. Chem. Lett. 2003, 13, 3415) and warmed to ambienttemperature. The crude reaction is diluted with aq. sodium bicarbonatesolution and extracted with ethyl acetate. The combined organic layer isdried over sodium sulfate, concentrated and purified by silica gelchromatography to provide tert-butyl3-(4-bromophenyl)-2,6-dioxopiperidine-1-carboxylate-3-d.

3-(4-Bromophenyl)piperidine-2,6-dione-3-d

A solution of tert-butyl3-(4-bromophenyl)-2,6-dioxopiperidine-1-carboxylate-3-d in DCM istreated with TFA (20 equiv.) at ambient temperature. Upon consumption ofthe starting material, the reaction is concentrated and purified bysilica gel chromatography to provide3-(4-bromophenyl)piperidine-2,6-dione-3-d.

Example 3: 3-(4-Bromophenyl)-3-fluoropiperidine-2,6-dione

tert-Butyl 3-(4-bromophenyl)-3-fluoro-2,6-dioxopiperidine-1-carboxylate

A solution of tert-butyl3-(4-bromophenyl)-2,6-dioxopiperidine-1-carboxylate in anhydrous THF at−78° C. is treated with lithium bis(trimethylsilyl)amide (1.1 equiv.)for 1 hour. N-fluorobenzenesulfonimide (Bioorg. Med. Chem. Lett. 2003,13, 3415) in a minimal amount of anhydrous THF is added and the reactionis warmed to ambient temperature then quenched. The crude reaction isextracted with ethyl acetate and the combined organic layer is driedover sodium sulfate, concentrated and purified by silica gelchromatography to provide tert-butyl3-(4-bromophenyl)-3-fluoro-2,6-dioxopiperidine-1-carboxylate.

3-(4-Bromophenyl)-3-fluoropiperidine-2,6-dione

A solution of tert-butyl3-(4-bromophenyl)-3-fluoro-2,6-dioxopiperidine-1-carboxylate in DCM istreated with TFA (20 equiv.) at ambient temperature. Upon consumption ofthe starting material, the reaction is concentrated and purified bysilica gel chromatography to provide3-(4-bromophenyl)-3-fluoropiperidine-2,6-dione.

Example 4: 3-Methyl-3-phenylpiperidine-2,6-dione

tert-Butyl 3-(4-bromophenyl)-3-methyl-2,6-dioxopiperidine-1-carboxylate

A solution of tert-butyl3-(4-bromophenyl)-2,6-dioxopiperidine-1-carboxylate in anhydrous THF at−78° C. is treated with lithium bis(trimethylsilyl)amide (1.1 equiv.)for 1 hour. Iodomethane in a minimal amount of anhydrous THF is addedand the reaction is warmed to ambient temperature then quenched. Thecrude reaction is extracted with ethyl acetate and the combined organiclayer is dried over sodium sulfate, concentrated and purified by silicagel chromatography to provide tert-butyl3-(4-bromophenyl)-3-methyl-2,6-dioxopiperidine-1-carboxylate.

3-Methyl-3-phenylpiperidine-2,6-dione

A solution of tert-butyl3-(4-bromophenyl)-3-methyl-2,6-dioxopiperidine-1-carboxylate in DCM istreated with TFA (20 equiv.) at ambient temperature. Upon consumption ofthe starting material, the reaction is concentrated and purified bysilica gel chromatography to provide3-methyl-3-phenylpiperidine-2,6-dione.

Example 5: 7-(4-Bromophenyl)-5-azaspiro[2.5]octane-4,6-dione

Methyl1-(2-(4-bromophenyl)-3-methoxy-3-oxopropyl)cyclopropane-1-carboxylate

Sodium hydride (1.1 equiv.) is suspended in THF and cooled to 0° C.Methyl 2-(4-bromophenyl)acetate (1 equiv.) is added dropwise and thereaction is mixed for 1 hour. Methyl1-(bromomethyl)cyclopropane-1-carboxylate (1 equiv.) is added dropwise.When the reaction is judged to be complete it is quenched with aq.ammonium chloride and extracted with ethyl acetate. The combined organiclayers are dried over sodium sulfate, concentrated and purified bysilica gel chromatography to provide methyl1-(2-(4-bromophenyl)-3-methoxy-3-oxopropyl)cyclopropane-1-carboxylate.(Eur JOC, 2015, (3), 556)

7-(4-Bromophenyl)-5-azaspiro[2.5]octane-4,6-dione

To a stirred solution of sodium amide, prepared in situ from sodiummetal and ammonia in the presence of a catalytic amount of iron(III)chloride in liquid ammonia, is added a solution of the methyl1-(2-(4-bromophenyl)-3-methoxy-3-oxopropyl)cyclopropane-1-carboxylate intetrahydrofuran at −33° C. The reaction is mixed for 3 h, then excessammonium chloride is added and the ammonia is allowed to evaporate.Water is then added to the residue and the mixture is extracted withchloroform. The combined organic layer is dried over sodium sulfate,concentrated and purified by silica gel chromatography to provide7-(4-bromophenyl)-5-azaspiro[2.5]octane-4,6-dione. (Synthesis, 1985,(4), 402)

Example 6: 1-(4-Bromophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

N-(4-Methoxbenzyl)acrylamide

To a 0° C. solution of (4-methoxyphenyl)methanamine (1 equiv.) andtrimethylamine (1.5 equiv.) in DCM is added dropwise acryloyl chloride(1.1 equiv.). The reaction is mixed for 1 hour then warmed to ambienttemperature. The reaction is quenched with aqueous bicarbonate and mixedfor 1 hour then extracted with DCM (3×). The combined organic layers aredried over sodium sulfate, filtered concentrated and purified by silicagel chromatography to provide N-(4-methoxybenzyl)acrylamide.(ChemMedChem, 2012, 7(12), 2082)

2-(4-Bromophenyl)Acrylic Acid

An aqueous solution of 1N sodium hydroxide (10 mL) is added to ethyl2-(4-bromophenyl)acrylate (5 mmol). The reaction mixture is heated atreflux for 1 hour and cooled to ambient temperature. The resultingmixture is extracted with diethyl ether several times (2×20 mL). Theaqueous layer is then acidified with 3N aqueous HCl solutions (pH<1.0 bylitmus paper test), and extracted with ethyl ether (3×20 mL). Thecombined organic extracts are dried over sodium sulfate, filtered andconcentrated. Crude 2-(4-bromophenyl)acrylic acid is dried under vacuumand air then used directly in subsequent reactions without furtherpurification. (J. Am. Chem. Soc. 2011, 133(6), 1726)

N-Acryloyl-2-(4-bromophenyl)-N-(4-methoxybenzyl)acrylamide

Crude 2-(4-bromophenyl)acrylic acid (1 equiv.) and (2 mol % DMF) aresuspended in DCM and cooled to 0° C. Oxalyl chloride (1.5 equiv.) wasadded dropwise. When the reaction clarifies it is warmed to ambienttemperature and mixed for an additional 2 hours. The resultant solutionis cooled to 0° C. and triethylamine (2 equiv.) andN-(4-methoxybenzyl)acrylamide (1 equiv.) are added. The reaction isstirred for an additional 1.5 hours then concentrated to dryness andpurified by silica gel chromatography to provideN-acryloyl-2-(4-bromophenyl)-N-(4-methoxybenzyl)acrylamide.

1-(4-Bromophenyl)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

A solution of N-acryloyl-2-(4-bromophenyl)-N-(4-methoxybenzyl)acrylamide(1 equiv.) and 2,6-di-tert-butyl-p-cresol (1.5 mol %) are heated at 170°C. in 1,2-dichlorobenzene for 1.5 hours. The reaction mixture is cooledand the volatiles removed by rotary evaporation and the residue purifiedby silica gel chromatography to provide1-(4-bromophenyl)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione.(J. Med. Chem. 1991, 34, 1329)

1-(4-Bromophenyl)-3-azabicyclo [3.1.1]heptane-2,4-dione

To a solution of1-(4-bromophenyl)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione(1 equiv.) dissolved in MeCN (0.1M) is added an aqueous solution ofcerium(IV)ammonium nitrate (3.75 equiv., 1.3M solution). The reaction ismixed for 4 hours then concentrated to half-volume. This solution isdiluted with ethyl acetate and saturated bicarbonate solution and mixedfor 0.5 hours. This mixture is filtered through Celite® and theresultant biphasic solution is separated and washed with brine. Thecombined aqueous layers are saturated with sodium chloride andback-extracted with ethyl acetate. The combined organic layers are driedover sodium sulfate, filtered, concentrated and purified by silica gelchromatography to provide1-(4-bromophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione. (J. Med. Chem.1991, 34, 1329)

3-((4-Bromophenyl)(hydroxy)methyl)piperidine-2,6-dione

To a stirred solution of piperidine-2,6-dione (1.0 equiv.) in DMF (5volumes) is added potassium carbonate (2 equiv.) at ambient temperature.The resulting solution is cooled to 5° C. and di-tert-butyl dicarbonate(3 equiv.) is added slowly as a solution in cold dioxane. The resultingmixture is stirred at 0° C. for 1 hour and allowed to warm to ambienttemperature overnight. Water (10 volumes) is then added and the aqueouslayer extracted with DCM (2×). The combined organic layer is dried oversodium sulfate, filtered and concentrated under vacuum to providetert-butyl 2,6-dioxopiperidine-1-carboxylate.

tert-Butyl3-((4-bromophenyl)(hydroxy)methyl)-2,6-dioxopiperidine-1-carboxylate

A solution of tert-butyl 2,6-dioxopiperidine-1-carboxylate in anhydrousTHF at −78° C. is treated with lithium diisopropylamide (1.1 equiv.) for1 hour. 4-Bromobenzaldehyde in a minimal amount of anhydrous THF isadded and the reaction is warmed to ambient temperature then quenchedwith aq. ammonium chloride. The crude reaction is extracted with ethylacetate and the combined organic layer is dried over sodium sulfate,concentrated and purified by silica gel chromatography to providetert-butyl3-((4-bromophenyl)(hydroxy)methyl)-2,6-dioxopiperidine-1-carboxylate.

A reaction vessel is charged with tert-butyl3-((4-bromophenyl)(hydroxy)methyl)-2,6-dioxopiperidine-1-carboxylate (1equiv.) and DCM (0.1 M). TFA (20 equiv.) is then added and the reactionis mixed for 1 hour at ambient temperature. The volatiles are removed byrotary evaporation and the residue purified by silica gel chromatographyto provide 3-((4-bromophenyl)(hydroxy)methyl)piperidine-2,6-dione.

3-(1-(4-Bromophenyl)-1-hydroxyethyl)piperidine-2,6-dione

A solution of tert-butyl 2,6-dioxopiperidine-1-carboxylate in anhydrousTHF at −78° C. is treated with lithium diisopropylamide (1.1 equiv.) for1 hour. 1-(4-bromophenyl)ethan-1-one in a minimal amount of anhydrousTHF is added and the reaction is warmed to ambient temperature thenquenched with aq. ammonium chloride. The crude reaction is extractedwith ethyl acetate and the combined organic layer is dried over sodiumsulfate, concentrated and purified by silica gel chromatography toprovide tert-butyl3-(1-(4-bromophenyl)-1-hydroxyethyl)-2,6-dioxopiperidine-1-carboxylate.

A reaction vessel is charged with tert-butyl3-(1-(4-bromophenyl)-1-hydroxyethyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) and DCM (0.1 M). TFA (20 equiv.) is then added and thereaction is mixed for 1 hour at ambient temperature. The volatiles areremoved by rotary evaporation and the residue purified by silica gelchromatography to provide3-(1-(4-bromophenyl)-1-hydroxyethyl)piperidine-2,6-dione.

3-(4-Bromobenzyl)piperidine-2,6-dione

A solution of tert-butyl 2,6-dioxopiperidine-1-carboxylate in anhydrousTHF at −78° C. is treated with lithium diisopropylamide (1.1 equiv.) for1 hour. 1-Bromo-4-(bromomethyl)benzene in a minimal amount of anhydrousTHF is added and the reaction is warmed to ambient temperature thenquenched with aq. ammonium chloride. The crude reaction is extractedwith ethyl acetate and the combined organic layer is dried over sodiumsulfate, concentrated and purified by silica gel chromatography toprovide tert-butyl 3-(4-bromobenzyl)-2,6-dioxopiperidine-1-carboxylate.

A reaction vessel is charged with tert-butyl3-(4-bromobenzyl)-2,6-dioxopiperidine-1-carboxylate (1 equiv.) and DCM(0.1 M). TFA (20 equiv.) is added and the reaction is mixed for 1 hourat ambient temperature. The volatiles are removed by rotary evaporationand the residue purified by silica gel chromatography to provide3-(4-bromobenzyl)piperidine-2,6-dione.

3-(2-(4-Bromophenyl)-2-hydroxypropyl)piperidine-2,6-dione

A solution of tert-butyl 2,6-dioxopiperidine-1-carboxylate in anhydrousTHF at −78° C. is treated with lithium diisopropylamide (1.1 equiv.) for1 hour. In a minimal amount of anhydrous THF is added2-(4-bromophenyl)-2-methyloxirane and the solution is added to thereaction. The reaction is warmed to ambient temperature then quenchedwith aq. ammonium chloride. The crude reaction is extracted with ethylacetate and the combined organic layer is dried over sodium sulfate,concentrated and purified by silica gel chromatography to providetert-butyl3-(2-(4-bromophenyl)-2-hydroxypropyl)-2,6-dioxopiperidine-1-carboxylate.

A reaction vessel is charged with tert-butyl3-(2-(4-bromophenyl)-2-hydroxypropyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) and DCM (0.1 M). TFA (20 equiv.) is then added and thereaction is mixed for 1 hour at ambient temperature. The volatiles areremoved by rotary evaporation and the residue purified by silica gelchromatography to provide3-(2-(4-bromophenyl)-2-hydroxypropyl)piperidine-2,6-dione.

3-(1-((4-Bromophenyl)amino)ethyl)piperidine-2,6-dione

a solution of tert-butyl 2,6-dioxopiperidine-1-carboxylate in anhydrousTHF at −78° C. is treated with lithium diisopropylamide (1.1 equiv.) for1 hour. In a minimal amount of anhydrous THF is added(E)-N-(4-bromophenyl)ethanimine and the solution is added to thereaction. The reaction is warmed to ambient temperature and quenchedwith aq. ammonium chloride. The crude reaction is extracted with ethylacetate and the combined organic layer is dried over sodium sulfate,concentrated and purified by silica gel chromatography to providetert-butyl3-(1-((4-bromophenyl)amino)ethyl)-2,6-dioxopiperidine-1-carboxylate.

A reaction vessel is charged with tert-butyl3-(1-((4-bromophenyl)amino)ethyl)-2,6-dioxopiperidine-1-carboxylate (1equiv.) and DCM (0.1 M). TFA (20 equiv.) is then added and the reactionis mixed for 1 hour at ambient temperature. The volatiles are removed byrotary evaporation and the residue purified by silica gel chromatographyto provide 3-(1-((4-bromophenyl)amino)ethyl)piperidine-2,6-dione.

3-(1-((4-Bromophenyl)amino)ethyl)piperidine-2,6-dione

A solution of tert-butyl 2,6-dioxopiperidine-1-carboxylate in anhydrousTHF at −78° C. is treated with lithium diisopropylamide (1.1 equiv.) for1 hour. In a minimal amount of anhydrous THF is added(E)-N-ethylidene-2-methylpropane-2-sulfinamide and the solution is addedto the reaction. The reaction is warmed to ambient temperature andquenched with aq. ammonium chloride. The crude reaction is extractedwith ethyl acetate and the combined organic layer is dried over sodiumsulfate, concentrated and purified by silica gel chromatography toprovide tert-butyl3-(1-((tert-butylsulfinyl)amino)ethyl)-2,6-dioxopiperidine-1-carboxylate.

A reaction vessel is charged with tert-butyl3-(1-((tert-butylsulfinyl)amino)ethyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) and 1,4-dioxane (0.1 M). HCl (4.0 M in dioxane, 1 equiv.) isthen added and the reaction is mixed for 1 hour at ambient temperature.The volatiles are removed by rotary evaporation and the residue purifiedby silica gel chromatography to provide tert-butyl3-(1-aminoethyl)-2,6-dioxopiperidine-1-carboxylate.

3-(1-((4-Bromophenyl)amino)ethyl)piperidine-2,6-dione

To a reaction vessel is added tert-butyl3-(1-((tert-butylsulfinyl)amino)ethyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.), 1,4-dibromobenzene (1 equiv), BretPhos Precatalyst (1 mol %)and sodium tert-butoxide (2 equiv.). The reaction vessel is sealed andthe atmosphere cycled between nitrogen and vacuum (3×). n-Butanol (0.5M) is added and the reaction is heated at 100° C. for 5 hours. Thereaction is cooled, diluted with ethyl acetate and filtered through aplug of Celite®. The filtrate is concentrated and purified by silica gelchromatography to provide tert-butyl3-(1-((4-bromophenyl)(tert-butylsulfinyl)amino)ethyl)-2,6-dioxopiperidine-1-carboxylate(J. Am. Chem. Soc. 2008, 130, 13552).

A reaction vessel is charged with tert-butyl3-(1-((4-bromophenyl)(tert-butylsulfinyl)amino)ethyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) and DCM (0.1 M). TFA (20 equiv.) is then added and thereaction is mixed for 1 hour at ambient temperature. The volatiles areremoved by rotary evaporation and the residue purified by silica gelchromatography to provide3-(1-((4-bromophenyl)amino)ethyl)piperidine-2,6-dione.

Intermediate functionalization in preparation for Linker installationtert-Butyl 3-(4-aminophenyl)-2,6-dioxopiperidine-1-carboxylate

A reaction vessel is charged with tert-butyl3-(4-bromophenyl)-3-fluoro-2,6-dioxopiperidine-1-carboxylate (1 equiv.),benzophenone imine (1.2 equiv.),tris(dibenzylideneacetone)dipalladium(0) (1 mol %), BINAP (3 mol %) andsodium tert-butoxide and purged by cycling between nitrogen and vacuum 3times. Toluene is added and the reaction is heated at 80° C. for 18hours. Ethyl acetate is added and the solids separated by filtrationthrough a plug of Celite®. The filtrate is concentrated and the residueis purified by chromatography to provide tert-butyl3-(4-((diphenylmethylene)amino)phenyl)-2,6-dioxopiperidine-1-carboxylate.

A reaction vessel is charged with tert-butyl3-(4-((diphenylmethylene)amino)phenyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) and dissolved in MeOH. Hydroxylamine hydrochloride (1.8equiv.) and sodium acetate (2.4 equiv.) are added and the reaction mixedat ambient temperature for 1 hour. The reaction is quenched by additionof 0.1M aq. NaOH solution and the resultant mixture extracted with ethylacetate. The combined organic layer is washed with brine, dried oversodium sulfate, filtered, and concentrated. The crude residue ispurified by silica gel chromatography to provide tert-butyl3-(4-aminophenyl)-2,6-dioxopiperidine-1-carboxylate. (PCT Int. Appl.,2015002230, 8 Jan. 2015)

tert-Butyl 3-(4-ethynylphenyl)-2,6-dioxopiperidine-1-carboxylate

A reaction vessel is charged with bis(triphenylphosphine)palladium(II)chloride (2 mol %), copper(I) iodide (4 mol %) and tert-butyl3-(4-bromophenyl)-3-fluoro-2,6-dioxopiperidine-1-carboxylate (1 equiv.).The reaction atmosphere is cycled between nitrogen and vacuum 3 timesthen triethylamine (1.55 equiv.) and trimethylsilylacetylene (1.25equiv.) are added and the reaction is mixed for 24 hours. When thestarting materials are consumed, the reaction is diluted with ethylacetate and filtered through a plug of Celite®. The filtrate isconcentrated and the residue is purified by silica gel chromatography toprovide tert-butyl2,6-dioxo-3-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylate.(Org. Lett. 2014, 16(24), 6302).

A reaction vessel is charged with tert-butyl2,6-dioxo-3-(4-((trimethylsilyl)ethynyl)phenyl)piperidine-1-carboxylate(1 equiv.), potassium carbonate (4 equiv.) and MeOH. The reaction ismixed at ambient temperature for 8 hours then concentrated. The residueis diluted with water and ethyl acetate. The aqueous layer is extractedwith ethyl acetate and the combined organic layer is dried over sodiumsulfate, filtered and concentrated. The crude residue is purified bysilica gel chromatography to provide tert-butyl3-(4-ethynylphenyl)-2,6-dioxopiperidine-1-carboxylate.

tert-Butyl 3-(4-hydroxyphenyl)-2,6-dioxopiperidine-1-carboxylate

A reaction vial is charged with tris(dibenzylideneacetone)dipalladium(0)(1 mol %),2-(di-adamantan-1-yl)phosphaneyl)-1-(2,6-diisopropylphenyl)-1H-imidazole(3 mol %), CsOH*H₂0 (3 equiv.). The vial is sealed, and the atmosphereis cycled between vacuum and nitrogen three times. Anhydrous THF andtert-butyl 3-(4-bromophenyl)-3-fluoro-2,6-dioxopiperidine-1-carboxylateare added and the reaction is mixed at ambient temperature for 20 hours.The reaction is then diluted with ethyl acetate, filtered throughCelite® and concentrated. The crude residue is purified by silica gelchromatography to provide tert-butyl3-(4-hydroxyphenyl)-2,6-dioxopiperidine-1-carboxylate. (Angew. Chem.Int. Ed. 2009, 48, 7595).

tert-Butyl2,6-dioxo-3-(4-(prop-2-yn-1-yloxy)phenyl)piperidine-1-carboxylate

A reaction vessel is charged with tert-butyl3-(4-hydroxyphenyl)-2,6-dioxopiperidine-1-carboxylate (1 equiv.) andacetone (0.25 M). To this solution is added sequentially potassiumcarbonate (4 equiv.) and propargyl bromide (1.2 equiv.). The reaction isheated at reflux overnight, cooled to ambient temperature, filteredthrough a medium frit, and concentrated. The crude residue is purifiedby silica gel chromatography to provide tert-butyl2,6-dioxo-3-(4-(prop-2-yn-1-yloxy)phenyl)piperidine-1-carboxylate. (J.Med. Chem. 2013, 56(7), 2828).

4-(1-(tert-Butoxycarbonyl)-2,6-dioxopiperidin-3-yl)benzoic acid

A flame-dried reaction vessel is charged with tert-butyl3-(4-bromophenyl)-3-fluoro-2,6-dioxopiperidine-1-carboxylate (1 equiv.)and the atmosphere is cycled between nitrogen and vacuum three times.Ether is added and the solution is cooled to −78° C. tert-Butyllithium(2 equiv.) is added dropwise, the reaction is mixed for 15 min thencarbon dioxide gas is bubbled through the solution for 15 min. Thereaction is warmed to ambient temperature allowing excess carbon dioxidegas to slowly evolve from solution. The reaction is quenched with 1 Maq. NaOH solution and washed with ether (2×). The pH of the aqueouslayer is adjusted to pH=3 and the aqueous layer is extracted with ethylacetate (3×). The combined organic layer is dried over sodium sulfateand concentrated to dryness with toluene (3×) to provide4-(1-(tert-butoxycarbonyl)-2,6-dioxopiperidin-3-yl)benzoic acid.

tert-Butyl 3-(4-(hydroxymethyl)phenyl)-2,6-dioxopiperidine-1-carboxylate

A reaction vessel is charged with4-(1-(tert-butoxycarbonyl)-2,6-dioxopiperidin-3-yl)benzoic acid (1equiv.), THF and cool to 0° C. Triethylamine (1.1 equiv.) andisobutylchloroformate (1.1 equiv.) are added and the reaction mixed atambient temperature for 1 hour. The reaction is filtered through amedium frit and cooled to 0° C. To the solution of mixed anhydride isadded a solution of sodium borohydride (2 equiv.) in MeOH. Upon completereduction to the corresponding benzylic alcohol, the reaction isconcentrated then treated with ethyl acetate and 10% aq. HCl. The phasesare separated and aqueous solution is extracted with ethyl acetate (3×).The combined organic layer is washed with 5% sodium bicarbonatesolution, dried over sodium sulfate, and concentrated. The residue ispurified by silica gel chromatography to provide tert-butyl3-(4-(hydroxymethyl)phenyl)-2,6-dioxopiperidine-1-carboxylate.

tert-Butyl 3-(4-formylphenyl)-2,6-dioxopiperidine-1-carboxylate

A reaction vessel is charged with tert-butyl3-(4-(hydroxymethyl)phenyl)-2,6-dioxopiperidine-1-carboxylate (1equiv.), manganese dioxide (10 equiv.) and DCM. The reaction is heatedat reflux overnight then cooled to ambient temperature and filtered. Thefiltrate is concentrated and purified by silica gel chromatography toprovide tert-butyl 3-(4-formylphenyl)-2,6-dioxopiperidine-1-carboxylate.

tert-Butyl 3-(4-(bromomethyl)phenyl)-2,6-dioxopiperidine-1-carboxylate

A reaction vessel is charged with tert-butyl3-(4-(hydroxymethyl)phenyl)-2,6-dioxopiperidine-1-carboxylate (1 equiv.)and DCM. The solution is cooled to 0° C. and N-bromosuccinimide (1.25equiv.) and triphenylphosphine (1.25 equiv.) are then added. Thereaction is mixed for 3 hours then concentrated. The crude residue ispurified by silica gel chromatography to provide tert-butyl3-(4-(bromomethyl)phenyl)-2,6-dioxopiperidine-1-carboxylate. (J. Med.Chem. 2015, 58(3), 1215).

tert-Butyl 3-(4-(azidomethyl)phenyl)-2,6-dioxopiperidine-1-carboxylate

Sodium azide (3 equiv.) is added to a solution of tert-butyl3-(4-(bromomethyl)phenyl)-2,6-dioxopiperidine-1-carboxylate (1 equiv.)in water and acetone (1:3, 0.25 M). The reaction is heated at 60° C. for6 hours. The reaction is cooled to ambient temperature and the solventremoved by rotary evaporation. The aqueous layer is extracted with DCM(3×) and the combined organic layer is dried over sodium sulfate andfiltered. The filtrate is concentrated and the crude residue is purifiedby silica gel chromatography to provide tert-butyl3-(4-(azidomethyl)phenyl)-2,6-dioxopiperidine-1-carboxylate. (Angew.Chem. Int. Ed. 2014, 53(38), 10155).

Linker Installation tert-Butyl3-(4-((8-hydroxyoctyl)oxy)phenyl)-2,6-dioxopiperidine-1-carboxylate

A reaction vessel is charged with tert-butyl3-(4-hydroxyphenyl)-2,6-dioxopiperidine-1-carboxylate (1 equiv.) and DMF(0.3 M) then cooled to 0° C. Sodium hydride (60% dispersion in mineraloil, 1.1 equiv.) is added and the reaction is warmed to ambienttemperature and mixed for 1 hour. The reaction is cooled to 0° C. then8-bromooctan-1-ol (1.1 equiv.) is added and the reaction is mixed atambient temperature overnight. DMF is removed by rotary evaporation andthe residue is deposited onto silica gel and purified by silica gelchromatography to provide tert-butyl3-(4-((8-hydroxyoctyl)oxy)phenyl)-2,6-dioxopiperidine-1-carboxylate.

tert-Butyl3-(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate

A reaction vessel is charged with tert-butyl3-(4-hydroxyphenyl)-2,6-dioxopiperidine-1-carboxylate (1 equiv.) and DMF(0.3 M) then cooled to 0° C. Sodium hydride (60% dispersion in mineraloil, 1.1 equiv.) is added and the reaction is warmed to ambienttemperature and mixed for 1 hour. The reaction is cooled to 0° C. then2-(2-(2-bromoethoxy)ethoxy)ethan-1-ol (1.1 equiv.) is added and thereaction is mixed at ambient temperature overnight. DMF is removed byrotary evaporation and the residue is deposited onto silica gel andpurified by silica gel chromatography to provide tert-butyl3-(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate.

tert-Butyl3-(4-((1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate

A reaction vessel is charged with the polymer supported catalyst(Amberlyst A-21, 1.23 mmol/g; Cu, 13% mol). The azide (0.5 M in DCM) isadded dropwise followed by a solution of the tert-butyl2,6-dioxo-3-(4-(prop-2-yn-1-yloxy)phenyl)piperidine-1carboxylate (0.5 Min DCM). The suspension is mixed for 12 hours at ambient temperature.The reaction solution is filtered through a frit and the polymer cake iswashed with DCM (2×). The combined filtrate is concentrated and theresidue purified by silica gel chromatography to provide tert-butyl3-(4-((1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate.(Org. Lett. 2006, 8(8), 1689).

tert-Butyl3-(4-(2-(2,4-dihydroxy-2-methylbutoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate

tert-Butyl3-(4-(2-hydroxyethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate

A reaction vessel is charged with tert-butyl3-(4-hydroxyphenyl)-2,6-dioxopiperidine-1-carboxylate (1 equiv.),potassium carbonate (2 equiv.) and DMF (0.5 M).2-(2-Chloroethoxy)tetrahydro-2H-pyran (1.1 equiv.) is added and thereaction is heated at 110° C. for 12 hours. The reaction is then cooledto ambient temperature and concentrated. The residue is taken up inwater and ethyl acetate and the layers separated. The aqueous layer isextracted with ethyl acetate (2×). The combined organic layer is washedwith brine, dried over sodium sulfate, filtered and concentrated. Thecrude residue is used directly in the following reaction.

A reaction vessel is charged with crude tert-butyl2,6-dioxo-3-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)piperidine-1-carboxylate(1 equiv.), MeOH and DCM (1:1, 0.2 M). p-Toluenesulfonic acid (0.1equiv.) is added and the reaction mixed at ambient temperature. Uponcompletion of the hydrolysis reaction, the volatiles are removed byrotary evaporation and the residue purified by silica gel chromatographyto provide tert-butyl3-(4-(2-hydroxyethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate.

tert-Butyl2,6-dioxo-3-(4-(2-(2-oxopropoxy)ethoxy)phenyl)piperidine-1-carboxylate

A reaction vessel is charged with tert-butyl3-(4-(2-hydroxyethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate (1equiv.), potassium carbonate (1.2 equiv.) and acetone (0.1 M).Chloroacetone (1.2 equiv.) is then added and the reaction heated atreflux overnight. The reaction is cooled then concentrated and the cruderesidue partitioned between water and ethyl acetate. The layers areseparated and the aqueous layer extracted with ethyl acetate (2×). Thecombined organic layers are dried over sodium sulfate, filtered andconcentrated. The crude residue is purified by column chromatography toprovide tert-butyl2,6-dioxo-3-(4-(2-(2-oxopropoxy)ethoxy)phenyl)piperidine-1-carboxylate.(J. Med. Chem. 2007, 50(18), 4304).

tert-Butyl3-(4-(2-(2,4-dihydroxy-2-methylbutoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate

A reaction vessel is charged with tert-butyl2,6-dioxo-3-(4-(2-(2-oxopropoxy)ethoxy)phenyl)piperidine-1-carboxylate(1 equiv.), and THF (0.2 M), purged with nitrogen and cooled to −78° C.Vinylmagnesium bromide (4 equiv.) is added dropwise and the reaction iswarmed to 0° C. over 1 hour. The reaction is quenched with aq. 1% HClsolution and extracted with ethyl acetate (3×). The combined organiclayer is washed with brine, dried over sodium sulfate, filtered andconcentrated. The crude residue is purified by silica gel chromatographyto provide tert-butyl3-(4-(2-((2-hydroxy-2-methylbut-3-en-1-yl)oxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate.

Cyclohexene (4.2 equiv.) was added to a solution of BH₃.THF (1 M in THF,2 equiv.) at 0° C. under argon. After stirring for 1 hour at 0° C., asolution of tert-butyl3-(4-(2-((2-hydroxy-2-methylbut-3-en-1-yl)oxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) in THF (0.15 M) was added to the mixture at 0° C. Afterstirring for 2 hours at 0° C., 3N NaOH (6 equiv.) and 30% H₂O₂ (33%volume of aq. NaOH solution addition) was added to the mixture. Thissolution is allowed to mix at ambient temperature for 30 min. Thereaction is quenched with saturated aqueous NH₄Cl (8 volumes) at 0° C.,and the resulting mixture is extracted with ethyl acetate (3×). Thecombined extracts are washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue ispurified by silica gel chromatography to provide tert-butyl3-(4-(2-(2,4-dihydroxy-2-methylbutoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate.(Org. Lett. 2012, 14(24), 6374).

tert-Butyl3-(4-((7-chloro-4-hydroxy-4-methylhept-2-yn-1-yl)oxy)phenyl)-2,6-dioxopiperidine-1-carboxylate

A reaction vessel is charged with tert-butyl2,6-dioxo-3-(4-(prop-2-yn-1-yloxy)phenyl)piperidine-1-carboxylate (1equiv.) and the atmosphere cycled between nitrogen and vacuum threetimes. Anhydrous THF (0.1 M) is added and the reaction cooled to −78° C.Butyllithium (1.05 equiv.) is added and the reaction is mixed for 15min. 5-Chloro-2-pentanone (1.1 equiv.) in THF (5 volumes) is then addedand the reaction is warmed to ambient temperature and quenched with sat.aq. ammonium chloride solution. Ethyl acetate is added and the phasesare separated. The aqueous layer is extracted with ethyl acetate (2×).The combined organic layers are washed with brine, dried over sodiumsulfate, filtered and concentrated. The crude residue is purified bysilica gel chromatography to provide tert-butyl3-(4-((7-chloro-4-hydroxy-4-methylhept-2-yn-1-yl)oxy)phenyl)-2,6-dioxopiperidine-1-carboxylate.

Examples of Final Compounds

d-Bromo

To a reaction vessel is addedN-(5-(8-amino-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-methylphenyl)methanesulfonamide(1 equiv.), trimethylamine (2 equiv.), THF (0.2 M) and CDI (1.05equiv.). The reaction is heated at reflux for 2 hours then cooled toambient temperature. tert-Butyl3-(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) in a minimal amount of THF is added and the reaction mixedovernight. The volatiles are removed by rotary evaporation and the cruderesidue purified by silica gel chromatography to provide tert-butyl3-(4-(2-(2-(2-(((3-methyl-6-(4-methyl-3-(methylsulfonamido)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)carbamoyl)oxy)ethoxy)ethoxy)-ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate.

A reaction vessel is charged with tert-butyl3-(4-(2-(2-(2-(((3-methyl-6-(4-methyl-3-(methylsulfonamido)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)carbamoyl)oxy)ethoxy)-ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) and DCM (0.1 M). TFA (20 equiv.) is then added and thereaction is mixed for 1 hour at ambient temperature. The volatiles areremoved by rotary evaporation and the residue purified by reverse phaseHPLC to provide d-Bromo.

d-BAZ2A/B

To a flask cooled at 0° C. containing1-(7-hydroxy-1-(2-(methylsulfonyl)phenyl)indolizin-3-yl)ethan-1-one (1equiv.), tert-butyl3-(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.), triphenylphosphine (2 equiv.) in THF (0.2 M) is addeddropwise diisopropyl azodicarboxylate (2 equiv.). The reaction is warmedto ambient temperature and mixed overnight. The volatiles are thenremoved by rotary evaporation and the crude residue purified by silicagel chromatography to provide tert-butyl3-(4-(2-(2-(2-((3-acetyl-1-(2-(methylsulfonyl)phenyl)indolizin-7-yl)oxy)ethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate.

A reaction vessel is charged with tert-butyl3-(4-(2-(2-(2-((3-acetyl-1-(2-(methylsulfonyl)phenyl)indolizin-7-yl)oxy)ethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) and DCM (0.1 M). TFA (20 equiv.) is then added and thereaction is mixed for 1 hour at ambient temperature. The volatiles areremoved by rotary evaporation and the residue purified by reverse phaseHPLC to provide d-BAZ2A/B.

d-Family VIII Bromo

tert-Butyl2,6-dioxo-3-(4-((3-oxo-1-phenyl-2,7,10-trioxa-4-azadodecan-12-yl)oxy)phenyl)piperidine-1-carboxylate

A reaction vessel is charged with tert-butyl3-(4-hydroxyphenyl)-2,6-dioxopiperidine-1-carboxylate (1 equiv.), DMF(0.3 M) and cooled to 0° C. Sodium hydride (60% dispersion in mineraloil, 1.1 equiv.) is added and the reaction is warmed to ambienttemperature and mixed for 1 hour. The reaction is cooled to 0° C. then8-bromooctan-1-ol (1.1 equiv.) is added and the reaction is mixed atambient temperature overnight. DMF is removed by rotary evaporation andthe residue is deposited onto silica gel and purified by silica gelchromatography to provide tert-butyl2,6-dioxo-3-(4-((3-oxo-1-phenyl-2,7,10-trioxa-4-azadodecan-12-yl)oxy)phenyl)piperidine-1-carboxylate.

tert-Butyl2,6-dioxo-3-(4-(2-(2-(2-(((6S,9R)-6,7,8,9-tetrahydro-5H-6,9-epimincyclohepta[d]pyrimidin-4-yl)amino)ethoxy)ethoxy)ethoxy)phenyl)piperidine-1-carboxylate

A reaction vessel is charged with tert-butyl2,6-dioxo-3-(4-((3-oxo-1-phenyl-2,7,10-trioxa-4-azadodecan-12-yl)oxy)phenyl)piperidine-1-carboxylate (1equiv.) and MeOH (0.2 M). The solution is purged with nitrogen for 5 min(needle in the solution), then Pd/C (10% wt, 10 mol %) is added and thesolution is purged for another 2 min. A balloon of hydrogen, fitted witha needle, is added to the flask and the nitrogen atmosphere of the flaskis purged with hydrogen. The reaction is mixed at ambient temperaturefor 2 hours then purged with nitrogen and filtered through a plug ofCelite®. The volatiles are removed by rotary evaporation and crudetert-butyl3-(4-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylateis used directly in the following reaction.

To a reaction vessel is added tert-butyl3-(4-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylat(1 equiv.),(6S,9R)-10-benzyl-4-chloro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine(1 equiv., DOI: 10.1021/acs.jmedchem.6b00012), BretPhos Precatalyst (1mol %) and sodium tert-butoxide (2 equiv.). The reaction vessel issealed and the atmosphere cycled between nitrogen and vacuum (3×).Dioxane (0.5 M) is added and the reaction is heated at 100° C. for 5hours. The reaction is cooled, diluted with ethyl acetate and filteredthrough a plug of Celite®. The filtrate is concentrated and purified bysilica gel chromatography to provide tert-butyl3-(4-(2-(2-(2-(((6S,9R)-10-benzyl-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidin-4-yl)amino)ethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate.(J. Am. Chem. Soc. 2008, 130, 13552).

An appropriate reaction vessel is charged with tert-butyl3-(4-(2-(2-(2-(((6S,9R)-10-benzyl-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidin-4-yl)amino)ethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) and MeOH (0.1 M). The solution is purged with nitrogen andPd/C is added. The solution is purged with nitrogen, the vessel sealedand the atmosphere purged with hydrogen. The reaction is pressurized to30 psi and mixed for 20 hours at ambient temperature. The hydrogen ispurged from the reaction with nitrogen and the solution filtered througha plug of Celite®. The filtrate is concentrated and purified by silicagel chromatography to provide tert-butyl2,6-dioxo-3-(4-(2-(2-(2-(((6S,9R)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidin-4-yl)amino)ethoxy)ethoxy)ethoxy)-phenyl)piperidine-1-carboxylate.

d-Family VIII Bromo

A reaction vessel is charged with tert-butyl2,6-dioxo-3-(4-(2-(2-(2-(((6S,9R)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidin-4-yl)amino)ethoxy)ethoxy)-ethoxy)phenyl)piperidine-1-carboxylate(1 equiv.), DIPEA (5 equiv.), chromone-3-carboxylic acid (1.2 equiv.)and ethanol (0.2 M). The reaction is stirred for 4.5 hours at ambienttemperature then heated at 50° C. for 5 hours. The reaction is cooled toambient temperature, concentrated, purified by silica gel chromatographyand used directly in the next step.

A reaction vessel is charged with tert-butyl3-(4-(2-(2-(2-(((6S,9R)-10-((E)-3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidin-4-yl)amino)ethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) and DCM (0.1 M). TFA (20 equiv.) is then added and thereaction is mixed for 1 hour at ambient temperature. The volatiles areremoved by rotary evaporation and the residue purified by silica gelchromatography to provide d-Family VIII Bromo.

d-CBP/EP300

tert-Butyl2,6-dioxo-3-(4-(2-(2-(2-oxoethoxy)ethoxy)ethoxy)phenyl)piperidine-1-carboxylate

A nitrogen-purged reaction vessel is charged with DMSO (3 equiv.) andDCM (0.1 M). The reaction is cooled to −78° C., oxalyl chloride (2equiv.) is added dropwise and the reaction is mixed for 0.5 hours.tert-Butyl3-(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) in a minimal amount of DCM is added, the reaction warmed to0° C. for 5 min then cooled to −78° C. and triethylamine (4 equiv.) isadded. The reaction is allowed to warm to ambient temperature slowlyovernight and then quenched with water. The biphasic mixture isseparated and the aq. layer extracted with DCM (2×). The combinedorganic layer is washed with brine, dried over sodium sulfate and useddirectly in the following reaction.

d-CBP/EP300

A reaction vessel is charged with tert-butyl2,6-dioxo-3-(4-(2-(2-(2-oxoethoxy)ethoxy)ethoxy)phenyl)piperidine-1-carboxylate(1 equiv.),(R)-1-(7-(3,4-dimethoxyphenyl)-9-(piperidin-3-ylmethoxy)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)propan-1-one(1 equiv.), sodium triacetoxyborohydride (3 equiv.) and DCE (0.2 M). Thereaction is heated at 50° C. for 3 hours then cooled to ambienttemperature and concentrated. The crude residue is purified by silicagel chromatography and used directly in the following step.

A reaction vessel is charged with tert-butyl3-(4-(2-(2-(2-((R)-3-(((7-(3,4-dimethoxyphenyl)-4-propionyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-yl)oxy)methyl)piperidin-1-yl)ethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) and DCM (0.1 M). TFA (20 equiv.) is then added and thereaction is mixed for 1 hour at ambient temperature. The volatiles areremoved by rotary evaporation and the residue purified by silica gelchromatography to provide d-CBP/EP300.

dFKBP*

tert-Butyl3-(4-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) is added to2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-(((S)-1-((S)-2-(3,4,5-trimethoxyphenyl)butanoyl)piperidine-2-carbonyl)oxy)propyl)phenoxy)acetic acid (1 equiv.) as asolution in DMF (0.1 M). DIPEA (3 equiv.) and HATU (1 equiv.) are addedand the mixture is stirred for 17 hours. The reaction is diluted withEtOAc and washed with saturated sodium bicarbonate, water and brine. Theorganic layer is then dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude residue is purified bysilica gel chromatography to provide tert-butyl3-(4-(2-(2-(2-(2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-(((S)-1-((S)-2-(3,4,5-trimethoxyphenyl)butanoyl)piperidine-2-carbonyl)oxy)propyl)phenoxy)acetamido)-ethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate.

A reaction vessel is charged with tert-butyl3-(4-(2-(2-(2-(2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-(((S)-1-((S)-2-(3,4,5-trimethoxyphenyl)butanoyl)piperidine-2-carbonyl)oxy)propyl)phenoxy)acetamido)ethoxy)ethoxy)ethoxy)phenyl)-2,6-dioxopiperidine-1-carboxylate(1 equiv.) and DCM (0.1 M). TFA (20 equiv.) is added and the reaction ismixed for 1 hour at ambient temperature. The volatiles are removed byrotary evaporation and the residue purified by silica gel chromatographyto provide(1R)-3-(3,4-dimethoxyphenyl)-1-(3-(2-((2-(2-(2-(4-(2,6-dioxopiperidin-3-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-2-oxoethoxy)phenyl)propyl(2S)-1-((S)-2-(3,4,5-trimethoxyphenyl)butanoyl)piperidine-2-carboxylate(d-FKBP*).

Additional Examples Preparation of Representative Targeting Ligands

(S)-6-(4-Chlorophenyl)-1,4-dimenthyl-8-(1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

tert-Butyl(R)-(1-((4-bromo-2-(4-chlorobenzoyl)phenyl)amino)-1-oxopropan-2-yl)carbamate

(2-Amino-5-bromophenyl)(4-chlorophenyl)methanone (1.0 equiv.) andBoc-(L)-Ala (1.0 equiv.) are suspended in DMF and cooled to 0° C. DIEA(2.0 equiv.) is added followed by HATU (1.1 equiv.) and the reaction isstirred at reduced temperature for 30 minutes and then warmed to roomtemperature. When the reaction is judged to be complete it is quenchedwith aq. ammonium chloride and extracted with ethyl acetate. Thecombined organic layers are dried over sodium sulfate, concentrated andpurified by silica gel chromatography to provide tert-butyl(R)-(1-((4-bromo-2-(4-chlorobenzoyl)phenyl)amino)-1-oxopropan-2-yl)carbamate.

(S)-7-Bromo-5-(4-chlorophenyl)-3-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one

To a stirred solution of Boc protected amine in CHCl₃ at r.t. is slowlyadded hydrogen chloride gas. After 20 minutes, the addition is stoppedand the reaction is stirred at r.t. until deprotection is complete. Thereaction mixture is washed with saturated bicarbonate solution (2×) andwater (2×). The organic layer is concentrated under reduced pressure.The residue is dissolved in 2:1 methanol:water and the pH is adjusted to8.5 by the addition of 1N aqueous NaOH. The reaction is then stirred atr.t. until the cyclization is complete. MeOH is then removed underreduced pressure and the solution is extracted with DCM (3×). Thecombined organic layer is dried over sodium sulfate, concentrated andpurified by silica gel chromatography to provide(S)-7-bromo-5-(4-chlorophenyl)-3-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one(US 2010 0261711).

(S)-8-Bromo-6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

A solution of diazapine (1.0 equiv.) in THF is cooled to −10° C. and NaH(0.85 equiv.) is added in one portion. After an hour at reducedtemperature di-4-morphilinylphosphinic chloride (1.07 equiv.) is addedat −10° C. and the reaction is allowed to warm to r.t. and stir for 2hours. To this mixture is added a solution of acetic hydrazide (1.4equiv.) in n-butanol and stirring is continued for 30 minutes. Thesolvent is then removed under reduced pressure and the residue dissolvedin fresh dry n-butanol before refluxing for the desired time frame. Uponcompletion of the reaction, the volatiles are removed by rotaryevaporation and the residue is partitioned between DCM and brine. Theorganic layer is dried, concentrated and purified by silica gelchromatography to provide(S)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine(US 2010 0261711).

(S)-6-(4-Chlorophenyl)-1,4-dimethyl-8-(1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

To a vial containing(S)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine(1 equiv.) is added Pd(PPh3)4 (20 mol %),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5equiv.), and potassium carbonate (2.5 equiv.). The vial is thenevacuated and purged under N₂. To the vial is added dioxane:water (2:1).The contents are once again evacuated and purged under N₂ and thereaction mixture heated at 80° C. until the SM is converted. The mixtureis then cooled to room temperature and filtered over a pad of Celite®.The filter pad is rinsed with EtOAc (3×) and the filtrate isconcentrate. The crude material is purified by flash chromatography (WO2015/156601).

(S)-4-(1,4-Dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)phenol

Methyl (R)-5-bromo-2-(2-(tert-butoxycarbonyl)amino)propanamido)benzoate

Methyl 2-amino-5-bromobenzoate (1.0 equiv.) and Boc-(L)-Ala (1.0 equiv.)is suspended in DMF and cooled to 0° C. DIEA (2.0 equiv.) is addedfollowed by HATU (1.1 equiv.) and the reaction is stirred at reducedtemperature for 30 minutes and then warmed to room temperature. When thereaction is judged to be complete it is quenched with aq. ammoniumchloride and extracted with ethyl acetate. The combined organic layersare dried over sodium sulfate, concentrated and purified by silica gelchromatography to provide methyl(R)-5-bromo-2-(2-((tert-butoxycarbonyl)amino)propanamido)benzoate.

Methyl5-bromo-2-(3-((R)-1-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-4H-1,2,4-triazol-4-yl)benzoate

Methyl (R)-5-bromo-2-(2-((tert-butoxycarbonyl)amino)propanamido)benzoate

A solution of methyl(R)-5-bromo-2-(2-((tert-butoxycarbonyl)amino)propanamido)benzoate (1.0equiv.) in THF is cooled to −10° C. and NaH (0.85 equiv.) is added inone portion. After an hour at reduced temperaturedi-4-morphilinylphosphinic chloride (1.07 equiv.) is added at −10° C.and the reaction is allowed to warm to r.t. and stir for 2 hours. Tothis mixture is added a solution of acetic hydrazide (1.4 equiv.) inn-butanol and stirring is continued for 30 minutes. The solvent is thenremoved under reduced pressure and the residue dissolved in fresh dryn-butanol before refluxing for the desired time frame. Upon completionof the reaction, the volatiles are removed by rotary evaporation and theresidue is partitioned between DCM and brine. The organic layer isdried, concentrated and purified by silica gel chromatography to providemethyl (R)-5-bromo-2-(2-((tert-butoxycarbonyl)amino)propanamido)benzoate(BMCL 2015, 25, 1842-48).

(S)-8-Bromo-1,4-dimethyl-4,5-dihydro-6H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-one

Methyl (R)-5-bromo-2-(2-((tert-butoxycarbonyl)amino)propanamido)benzoateis dissolved in DCM and cooled to 0° C. 4M HCl in dioxane is added andthe reaction is warmed to r.t. When deprotection is complete, thereaction is concentrated and then azeotroped from toluene (2×). Thecrude amine salt is then dissolved in THF, cooled to −40° C., at whichtime iPrMgBr solution is added dropwise (2.0 equiv.) and the reaction isstirred at reduced temp until complete conversion (BMCL 2015, 25,1842-48).

(S)-1,4-Dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-4,5-dihydro-6H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-one

To a vial containing(S)-8-bromo-1,4-dimethyl-4,5-dihydro-6H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-one(1 equiv.) is added Pd₂(dba)₃ (10 mol %), tri-tert-butylphosphoniumtetrafluoroborate (20 mol %),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.5 equiv.), and potassium phosphate tribasic, monohydrate (2.5equiv.). The vial is then evacuated and purged under N₂. To the vial isadded 20:1 ratio by volume of dioxane:water. The contents are once againevacuated and purged under N₂ (g) and the reaction mixture is heated at100° C. until the SM is converted. The mixture is then cooled to roomtemperature and filtered over a pad of Celite®. The filter pad is rinsedwith EtOAc (3×) and the filtrate is concentrate. The crude material ispurified by flash chromatography.

(S)-6-Chloro-1,4-dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

(S)-1,4-dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-4,5-dihydro-6H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-one(1.0 equiv.) is dissolved in DCM and PCl₅ (1.7 equiv.) is added inone-portion. After conversion of SM, 2M sodium carbonate is added. Thebiphasic mixture is subsequently extracted with EtOAc (4×). The combinedorganic layers are dried over sodium sulfate and concentrated todryness. The resultant residue is purified by flash chromatography.

(S)-4-(1,4-Dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)phenol

To a vial containing((S)-6-chloro-1,4-dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine(1 equiv.) is added Pd(PPh₃)₄ (20 mol %), 4-hydroxy-phenyl boronic acid(1.5 equiv.), and sodium carbonate (2.5 equiv.). The vial is thenevacuated and purged under N₂. To the vial is added tol:DME:water(1:1:5). The contents are once again evacuated and purged under N₂ andthe reaction mixture is heated at 80° C. until the SM is converted. Themixture is then cooled to room temperature and filtered over a pad ofCelite®. The filter pad is rinsed with EtOAc (3×) and the filtrate isconcentrate. The crude material is purified by flash chromatography.

Synthesis of Selected Glutarimides

C-Linked Experimentals III. Representative Synthesis of Compounds

Diethyl 1-phenylcyclopropane-1,2-dicarboxylate (1-1) (200 mg, 0.76 mmol)(prepared according to Epstein, J. W. et al. J. Med. Chem. 1981, 24,481-490.) and urea (91.2 mg, 1.52 mmol) were combined in xylene (10 mL)and stirred at 150° C. for 4 h. The solution was concentrated under highvacuum. The residue was diluted with MTBE (25 mL). The solution waswashed with aqueous saturated sodium bicarbonate (10 mL×2), dried(Na₂SO₄), and concentrated. The residue was purified by chromatographyusing EtOAc:hexanes=0:1 to 1:2 to give1-phenyl-3-azabicyclo[3.1.0]hexane-2,4-dione (Compound 1) (84 mg, 59%yield). ¹H NMR (400 MHz, Chloroform-d) δ 7.43-7.31 (m, 5H), 2.71 (ddd,J=8.4, 3.6, 1.8 Hz, 1H), 1.99 (dd, J=4.7, 3.6 Hz, 1H), 1.88 (dd, J=8.4,4.7 Hz, 1H). MS (observed) 188.1

Synthesis of3-(4-Methoxybenzyl)-1-phenyl-3-azabicyclo[3.1.1]heptane-2,4-dione (2-2)

To a solution of 2-phenylacrylic acid (2-1) (3.7 g, 24.9 mmol) in DMF(77 uL, 1.0 mmol) and DCM (40 ml) was added oxalyl chloride (2.55 mL,29.8 mmol) over 60 min at room temperature. The mixture was stirred for4 h, concentrated under reduced pressure, and dried under high vacuum.The residue was dissolved in DCM (20 mL) and slowly added into asolution of N-(4-methoxybenzyl)acrylamide (3.80 g, 19.9 mmol) and Et₃N(7.62 mL, 54.7 mmol) in DCM (20 mL) at −5° C. The mixture was stirred at0° C. for 1 h and then 35° C. for 3 h. The solution was cooled to roomtemperature, washed with aqueous saturated sodium bicarbonate (40 ml×3),dried (Na₂SO₄), and concentrated. The residue was purified bychromatography using EtOAc:hexanes=0:1 to 15:85 to give3-(4-methoxybenzyl)-1-phenyl-3-azabicyclo[3.1.1]heptane-2,4-dione (2-2)2.84 g in 35.5% yield. MS (observed) 322.2

Synthesis of3-(4-Methoxybenzyl)-1-phenyl-3-azabicyclo[3.1.1]heptane-2,4-dione (2-3)

3-(4-Methoxybenzyl)-1-phenyl-3-azabicyclo[3.1.1]heptane-2,4-dione (2-2)(3.04 g, 9.45 mmol) and BHT (41.6 mg, 0.19 mmol) were combined in1,2-dichlorobenzene (60 mL) and stirred at 170° C. for 4 h. The solutionwas concentrated. The residue was purified by chromatography usingEtOAc:hexanes=0:1 to 15:85 to 35:65 to give3-(4-methoxybenzyl)-1-phenyl-3-azabicyclo[3.1.1]heptane-2,4-dione (2-3)2.21 g in 72.9% yield. MS (observed) 322.3

Synthesis of 1-Phenyl-3-azabicyclo[3.1.1]heptane-2,4-dione (Compound 2)

To 3-(4-methoxybenzyl)-1-phenyl-3-azabicyclo[3.1.1]heptane-2,4-dione(597 mg, 1.86 mmol) in MeCN (4.5 mL) was added CAN (1.01 g, 1.86 mmol)and water (3 ml) at 0° C. The mixture was slowly warmed up to roomtemperature, stirred for 4 h at room temperature, and concentrated underreduced pressure. MTBE (40 mL) was added. The solution was washed withaqueous saturated ammonium chloride (10 ml×2), dried (Na₂SO₄), andconcentrated. The residue was purified by chromatography usingEtOAc:hexanes=0:1 to 1:1 to give the crude product, which was furtherpurified by Prep-HPLC to give provide1-phenyl-3-azabicyclo[3.1.1]heptane-2,4-dione (Compound 2), 21.9 mg in5.9% yield. ¹H NMR (400 MHz, Chloroform-d) δ 7.76-7.27 (m, 4H), 7.10 (d,J=7.5 Hz, 2H), 3.19 (dt, J=7.1, 3.5 Hz, 1H), 2.80 (ddt, J=14.2, 7.1, 4.2Hz, 4H). MS (observed) 202.1

Synthesis of 1-(4-Nitrophenyl)cyclopropane-1,2-dicarboxylic acid (3-2)

EtOH (0.03 mL) was added to a solution of NaH (152 mg, 3.81 mmol, 60%wt) in Et₂O (10 mL) at room temperature. A solution of ethyl2-bromo-2-(4-nitrophenyl)acetate (3-1) (1 g, 3.47 mmol), ethyl acrylate(0.74 mL, 6.94 mmol), and EtOH (0.20 mL) in Et₂O (5 mL) was added over 2h. The resulting solution was stirred at RT overnight and then quenchedwith saturated ammonium chloride (2 mL). MTBE (50 mL) was added. Themixture was washed with saturated ammonium chloride (10 mL×2) andconcentrated. The residue was purified by chromatography usingEtOAc:hexanes=0:1 to 15:85 to give the diester (556 mg) in 52% yield. Tothe Diester (556 mg, 1.8 mmol) in EtOH/Water (1:1, 10 mL) was added KOH(302 mg, 5.4 mmol) at room temperature. The mixture was stirred at 70°C. overnight. The solution was concentrated. The residue was dilutedwith hydrochloric acid (2 N, 18 mL). After extraction with EtOAc (20mL×3), the organic solution was dried (Na₂SO₄) and concentrated toprovide 1-(4-nitrophenyl)cyclopropane-1,2-dicarboxylic acid (3-2), whichwas used directly in the following reaction. MS (observed) 252.1

Synthesis of 1-(4-Nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(Compound 3)

To a rbf containing 1-(4-nitrophenyl)cyclopropane-1,2-dicarboxylic acid3-2 (452 mg, 1.8 mmol) and urea (216 mg, 3.6 mmol) was added xylene (12ml). The mixture was stirred at 150° C. for 4 h and concentrated underhigh vacuum. The residue was diluted with MTBE (25 mL). The resultingsolution was washed with aqueous saturated sodium bicarbonate (10 mL×2),dried (Na₂SO₄), and concentrated. The residue was purified bychromatography using EtOAc:hexanes=0:1 to 1:2 to give1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (Compound 3) 304mg in 73% yield. ¹H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.22 (d,J=8.8 Hz, 2H), 7.78 (dd, J=171.1, 8.8 Hz, 2H), 3.06 (dd, J=8.4, 3.9 Hz,1H), 2.16 (t, J=4.3 Hz, 1H), 2.00 (dd, J=8.4, 4.7 Hz, 1H). MS (observed)233.1

Synthesis of 1-(4-Aminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(Compound 4)

To a rbf containing1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (Compound 3) (50mg, 0.22 mmol) and Pd/C (13 mg, 0.01 mmol, 10% wt) was added EtOAc (3mL). The mixture was purged with hydrogen for 3 times and stirred underhydrogen for 3 hr. Pd/C was filtered with celite, and the solution wasconcentrated. The residue was purified by chromatography usingEtOAc:hexanes=0:1 to 4:1 to give crude product 30 mg with someimpurities. The residue was purified by Prep-HPLC to give1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (Compound 4) as aTFA salt 25.9 mg in 60% yield. ¹H NMR (400 MHz, DMSO-d6) δ 10.64 (s,1H), 7.38-7.29 (m, 2H), 7.01-6.88 (m, 2H), 2.75 (ddd, J=8.3, 3.7, 1.7Hz, 1H), 1.95 (t, J=4.2 Hz, 1H), 1.82 (dd, J=8.3, 4.2 Hz, 1H). MS(observed) 203.2

To 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (Compound 4)(19.8 mg, 0.10 mmol) in CH₂Cl₂ (2.5 mL) was added Et₃N (13.9 uL, 0.21mmol) at room temperature. The mixture was cooled to 0° C.Dimethylaminoacetyl chloride hydrochloride (17.0 mg, 0.11 mmol) wasadded. The mixture was slowly warmed to room temperature and stirredovernight. Additional Et₃N (13.9 uL, 0.21 mmol) and dimethylaminoacetylchloride hydrochloride (17.0 mg, 0.11 mmol) were added and the mixturewas stirred for 4 h. CH₂Cl₂ (5 mL) was added. The mixture was washedwith water (2 ml×2), dried (Na₂SO₄), and concentrated. The residue waspurified by Prep-HPLC to give2-(dimethylamino)-N-(4-(2,4-dioxo-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)acetamide(Compound 5) as TFA salt 17.6 mg in 63% yield. ¹H NMR (400 MHz, DMSO-d₆)δ 10.70 (s, 1H), 10.62 (s, 1H), 9.80 (s, 1H), 7.61-7.51 (m, 2H),7.50-7.39 (m, 2H), 4.14 (s, 2H), 2.88 (s, 6H), 2.82 (ddd, J=8.4, 3.7,1.6 Hz, 1H), 2.01 (t, J=4.3 Hz, 1H), 1.86 (dd, J=8.4, 4.3 Hz, 1H). MS(observed) 288.2

To 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (Compound 4)(20 mg, 0.10 mmol) in CH₂Cl₂ (2.5 mL) was added Et₃N (6.7 uL, 0.10 mmol)at room temperature. The mixture was cooled to 0° C. Acetyl chloride(7.0 uL, 0.10 mmol) was added. The mixture was slowly warmed up to roomtemperature and stirred overnight. CH₂Cl₂ (5 mL) was added. The mixturewas washed with water (2 ml×2), dried (Na₂SO₄), and concentrated. Theresidue was purified by Prep-HPLC to giveN-(4-(2,4-dioxo-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)acetamide (Compound6), 5.1 mg in 21% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 10.66 (s, 1H), 9.98(s, 1H), 7.55 (d, J=8.7 Hz, 2H), 7.38-7.33 (m, 2H), 2.78 (ddd, J=8.4,3.7, 1.7 Hz, 1H), 1.97 (dd, J=4.4, 3.7 Hz, 1H), 1.84 (dd, J=8.4, 4.4 Hz,1H). MS (observed) 245.1

To 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (Compound 4)(19.8 mg, 0.10 mmol) in CH₂Cl₂ (1 mL) was added Et₃N (7.92 uL, 0.12mmol). The mixture was cooled to 0° C. Methanesulfonic anhydride (18.8mg, 0.11 mmol) was added. The mixture was slowly warmed to roomtemperature and stirred overnight. Additional Et₃N (13.9 uL, 0.21 mmol)and methanesulfonic anhydride (18.8 mg, 0.11 mmol) were added. Themixture was stirred for another 4 h, diluted with CH₂Cl₂ 5 mL, washedwith water (2 mL×2), and concentrated. The residue was purified byPrep-HPLC to giveN-(4-(2,4-dioxo-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)methanesulfonamide(Compound 7), 2.81 mg in 10.2% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 10.68(s, 1H), 9.81 (s, 1H), 7.41 (d, J=8.6 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H),2.99 (s, 3H), 2.80 (ddd, J=8.4, 3.7, 1.7 Hz, 1H), 1.99 (t, J=4.3 Hz,1H), 1.85 (dd, J=8.4, 4.3 Hz, 1H). MS (observed) 281.2

Synthesis of 2-Methyl-2-phenylpentanedioic acid (7-2)

Ethyl 4-cyano-4-phenylpentanoate 7-1 (Prepared according to Battye, P.J.; Jones, D. W. J. Chem. Soc., Perkin Trans. 1: Organic and Bio-OrganicChemistry, 1986, 8, 1479-1489.) (1.17 g, 5.05 mmol), KOH (1.70 g, 30.3mmol), EtOH (1 mL) and water (12 mL) were stirred at 110° C. overnight.The mixture was cooled to room temperature and acidified (pH=2) withconcentrated HCl. The product was extracted with EtOAc (15 ml×3). Theorganic layers were combined, dried (Na₂SO₄) and concentrated to provide2-methyl-2-phenylpentanedioic acid 7-2 which was used directly in thenext step. MS (observed) 221.1

Synthesis of 3-Methyl-3-phenylpiperidine-2,6-dione (Compound 8)

2-Methyl-2-phenylpentanedioic acid 7-2 (1.12 g, 5.05 mmol) and urea (606mg, 10.1 mmol) in xylene (24 mL) were stirred at 150° C. overnight. Themixture was concentrated under high vacuum. The residue was diluted withEtOAc (40 mL), washed with brine (15 ml×2), dried (Na₂SO₄), andconcentrated. The residue was purified by chromatography usingEtOAc:hexanes=0:1 to 1:2 to give 3-methyl-3-phenylpiperidine-2,6-dione(Compound 8), 590 mg in 57% yield. ¹H NMR (500 MHz, Chloroform-d) δ 7.89(s, 1H), 7.39-7.21 (m, 4H), 2.55 (dddd, J=17.8, 4.4, 3.0, 0.9 Hz, 1H),2.41 (ddd, J=13.8, 4.9, 3.0 Hz, 1H), 2.31 (ddd, J=17.8, 12.9, 4.9 Hz,1H), 2.13 (ddd, J=13.8, 12.9, 4.4 Hz, 1H), 1.57 (s, 3H). MS (observed)204.1

Synthesis of 3:2 ratio of3-Methyl-3-(4-nitrophenyl)piperidine-2,6-dione:3-methyl-3-(2-nitrophenyl)piperidine-2,6-dione (Compound mixture 9(regioisomers)

A solution of H₂SO₄ (3 mL) and HNO₃ (217 mg, 2.35 mmol) were cooled to0° C. 3-Methyl-3-phenylpiperidine-2,6-dione (Compound 8) (400 mg, 1.96mmol) was added. The mixture was stirred at 0° C. for 10 min and thenreverse quenched into aqueous saturated sodium bicarbonate (30 mL). MTBE40 mL was added, the mixture was stirred for 30 min, and the organiclayer was separated. The aqueous layer was extracted with MTBE (20ml×2). All organic layers were combined and concentrated. The residuewas purified by chromatography using EtOAc:hexanes=0:1 to 3:2. A mixtureof regioisomers were obtained in 440 mg, yield 91%—ratio of3-Methyl-3-(4-nitrophenyl)piperidine-2,6-dione:3-methyl-3-(2-nitrophenyl)piperidine-2,6-dione=3:2 (Compound mixture 9).¹H NMR (400 MHz, Chloroform-d) δ 8.34-8.24 (m, 1H), 8.24-8.19 (m, 1H),8.13 (s, 1H), 7.70-7.57 (m, 1H), 7.57-7.44 (m, 1H), 2.75-2.64 (m, 1H),2.56-2.46 (m, 1H), 2.36 (dddd, J=17.0, 13.5, 12.1, 4.3 Hz, 1H),2.29-2.20 (m, 1H), 1.67 (s, 3H). MS (observed) 249.1

Synthesis of 3-(4-Aminophenyl)-3-methylpiperidine-2,6-dione (Compound10) and 3-(2-aminophenyl)-3-methylpiperidine-2,6-dione (Compound 11)

To a 3:2 mixture of 3-Methyl-3-(4-nitrophenyl)piperidine-2,6-dione and3-methyl-3-(2-nitrophenyl)piperidine-2,6-dione (Compound mixture 9) (200mg, 0.81 mmol) and Pd/C (42.6 mg, 0.4 mmol, 10% wt) in a 25 mL roundbottom flask was added EtOAc (4 mL). The mixture was purged with H₂ (3times). The solution was stirred overnight at room temperature. Themixture was filtered with celite, concentrated, and purified bychromatography using EtOAc:hexanes=0:1 to 3:1. Two regioisomers wereseparated as TFA salts by prep-HPLC to provide3-(4-aminophenyl)-3-methylpiperidine-2,6-dione (Compound 10), 51 mg and3-(2-aminophenyl)-3-methylpiperidine-2,6-dione (Compound 11), 25 mg.

Compound 10:

¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.24(d, J=8.7 Hz, 2H), 2.50-2.28 (m, 1.5H), 2.16-1.99 (m, 2.5H), 1.44 (s,4H). MS (observed) 219.2

Compound 11:

¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.01(d, J=7.9 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.1 Hz, 1H),2.47-2.26 (m, 2H), 2.18-2.00 (m, 2H), 1.43 (s, 3H). MS (observed) 219.2

To a stirred solution of 9-1 (100.0 mg, 884 μmol) in THF (7 mL) wasadded LiHMDS (1.94 mL, 1.94 mmol) at −40° C. The solution was stirred at−40° C. for 5-10 minutes followed by the addition of a THF solution (1mL) of 9-2 (159 mg, 884 μmol). The reaction mixture was stirred at −40°C. for 15 minutes and then it was allowed to warm up to room temperatureover 1.5 hours. Aqueous saturated aqueous NH₄Cl solution was added tothe reaction and the resulting solution was extracted with Ethylacetate. The combined Ethyl acetate extracts were washed with water,brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude mass was purified on a preparative TLC plate(eluting with 2% MeOH in DCM) to afford Compound 12 (35.0 mg, 136 μmol,15%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (s, 1H),7.52 (dd, J=17.4, 7.8 Hz, 2H), 7.17 (dt, J=21.5, 7.4 Hz, 2H), 3.76 (s,3H), 3.43 (dd, J=16.3, 4.2 Hz, 1H), 3.23-3.15 (m, 1H), 3.00 (dd, J=15.9,8.4 Hz, 1H), 2.66-2.50 (m, 2H), 2.00 (s, 2H). LC MS: ES+ 258.2.

To a stirred solution of 3-(chloromethyl)-1-methyl-1H-indazole 10-1 (135mg, 751 μmol) in THF (7.0 mL) was added LiHMDS (1.65 mL, 1.65 mmol) at−40° C. and piperidine-2,6-dione 9-1 (85.0 mg, 751 μmol) in THF (3.0 mL)was then added to the reaction mixture after 5 minutes. The reactionmixture was stirred at −40° C. for 15 minutes and then was allowed towarm up to room temperature over 1.5 hour. TLC showed formation of a newspot (Rf-0.3 in 5% MeOH/DCM). The reaction was quenched with saturatedaqueous NH₄Cl solution and extracted with ethyl acetate. The organicswere washed with water, brine, dried over sodium sulfate andconcentrated. The crude material was purified on a Prep TLC Plate(eluting with 2% MeOH/DCM) to afford3-((1-methyl-1H-indazol-3-yl)methyl)piperidine-2,6-dione (Compound 13)(30.0 mg, 116 μmol, 15.5%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d6) δ 10.71 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.4 Hz,1H), 7.37 (t, J=7.8 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 3.98 (s, 3H), 3.49(d, J=13.6 Hz, 1H), 3.07-2.96 (m, 2H), 2.50-2.43 (m, 2H), 1.78-1.72 (m,2H). LC MS: ES+258.3.

Synthesis of 2,6-Dioxo-piperidine-3-carboxylic acid tert-butyl ester(11-1)

To a stirred solution of 9-1 (3.5 g, 30.9 mmol) in THF (30.0 mL) at −78°C. was added LDA (15.45 mL, 30.9 mmol). After stirring for 10 minutes atthe same temperature, (Boc)₂O (7.05 mL, 30.9 mmol) was added and thereaction mixture was stirred for another 30 minutes at same temperature.Then again, LDA (15.45 mL, 30.9 mmol) was added to the reaction mixture,followed by (Boc)₂O (7.05 mL, 30.9 mmol) after 5 minutes. Thetemperature of the reaction was allowed to warm to room temperature over1 hour. The reaction was quenched with saturated aqueous NH₄Cl solutionand then extracted with ethyl acetate. The organic layer was washed withwater, brine, dried over sodium sulfate and concentrated. The crudematerial was purified by column chromatography using (silica, 100-200,0%-20% ethyl acetate/hexane) to afford 11-1 (1.50 g, 7.03 mmol, 22.7%)as off white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.90 (brs, 1H),3.55-3.52 (m, 1H), 2.56-2.50 (m, 1H), 2.45-2.38 (m, 1H), 2.11-2.01 (m,2H), 1.42 (s, 9H).

Synthesis of 2,6-Dioxo-piperidine-3-carboxylic acid (11-2)

To a stirred solution of 11-1 (1.0 g, 4.68 mmol) in DCM (15.0 mL) wasadded TFA (5.08 mL, 46.8 mmol) and the reaction mixture was stirred atroom temperature for 2 hours. The reaction was concentrated underreduced pressure and then triturated with ether to afford 11-2 (650 mg,4.13 mmol, 88.4%) as an off-white solid. LC MS: ES+ 158.1.

To a stirred solution of 11-2 (50.0 mg, 318 μmol) in DMF (1.0 mL) wasadded 12-1 (29.0 μL, 318 μmol), DIPEA (234 μL, 1.27 mmol) and HATU (181mg, 477 μmol). The reaction mixture was then stirred at room temperaturefor 16 hours. The reaction mixture was diluted with ethyl acetate andthe organic layer was washed with saturated aqueous NaHCO₃ solution,water, brine and dried over sodium sulfate. The organics wereconcentrated and the crude material was purified on a Prep TLC Plate(eluting with 2% Methanol/DCM) to afford Compound 14 (20.0 mg, 86.1μmol, 27.1%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H),10.26 (s, 1H), 7.63-7.56 (d, J=8.0 Hz, 2H), 7.32 (t, J=8.0 Hz, 2H), 7.07(td, J=7.4, 1.3 Hz, 1H), 3.62 (dd, J=8.3, 6.2 Hz, 1H), 2.57 (t, J=6.6Hz, 2H), 2.16 (p, J=6.5, 6.1 Hz, 2H). LC MS: ES+231.45.

The following compounds were synthesized by the general procedure inScheme 12:

Compound 15: Yield=31%, ¹H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.59(s, 1H), 8.01 (d, J=8.12 Hz, 1H), 7.04-7.11 (m, 2H), 6.91 (t, J=6.76 Hz,1H), 3.93 (t, J=6.88 Hz, 1H), 3.84 (s, 3H), 2.52-2.55 (m, 2H), 2.12-2.16(m, 2H). LC MS: ES+ 263.3

Compound 16: Yield=67%, ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.49(s, 1H), 8.74 (s, 1H), 8.28 (d, J=3.92 Hz, 1H), 8.05 (d, J=8.24 Hz, 1H),7.35-7.38 (m, 1H), 3.65 (t, J=6.84 Hz, 1H), 2.56-2.58 (m, 2H), 2.14-2.17(m, 2H). LC MS: ES+ 234.1

Compound 17: Yield=24%, ¹H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 10.77(s, 1H), 8.33 (s, 1H), 8.06 (d, J=8.12 Hz, 1H), 7.78-7.80 (m, 1H), 7.13(brs, 1H), 3.82 (brs, 1H), 2.52-2.54 (m, 2H), 2.13-2.16 (m, 2H). LC MS:ES+ 234.1

Compound 18: Yield=31%, ¹H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.07(s, 1H), 7.90-7.94 (m, 1H), 7.24-7.29 (m, 1H), 7.16-7.18 (m, 2H), 3.84(t, J=7.20 Hz, 1H), 2.54-2.57 (m, 2H), 2.12-2.17 (m, 2H). LC MS: ES+251.1

Compound 19: Yield=23%, ¹H NMR (400 MHz, DMSO-d6 at 100° C., rotamersobserved at 20° C.) δ 10.38 (br, 1H), 7.30-7.38 (m, 2H), 7.16 (d, J=8.04Hz, 1H), 7.02 (m, 1H), 3.85 (s, 3H), 3.35 (brs, 1H), 3.11 (s, 3H),2.40-2.52 (m, 2H), 1.85-2.02 (m, 2H). LC MS: ES+ 277.3

Compound 20: Yield=10%, ¹H NMR (400 MHz, CD3OD) δ 8.50 (d, J=3.60 Hz,1H), 7.92-7.96 (m, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.37-7.41 (m, 1H), 3.37(s, 3H), 2.62-2.67 (m, 1H), 2.48-2.52 (m, 1H), 2.23-2.29 (m, 1H),2.09-2.14 (m, 1H). LC MS: ES+ 248.1

Compound 21: Yield=20%, ¹H NMR (400 MHz, DMSO-d6 at 100° C., rotamersobserved at 20° C.) δ 10.47 (br, 1H), 7.29-7.46 (m, 4H), 3.46 (br, 1H),3.21 (brs, 3H), 2.50-2.66 (m, 2H), 1.95-2.06 (m, 2H). LC MS: ES+ 265.2

Compound 22: Yield=16%, ¹H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H),7.38-7.48 (m, 5H), 3.44-3.46 (m, 1H), 3.19 (s, 3H), 2.42-2.48 (m, 2H),2.01-2.05 (m, 1H), 1.88-1.93 (m, 1H); LC MS: ES+ 247.3.

Synthesis of (2,6-Dioxo-piperidin-3-yl)-acetic acid tert-butyl ester(13-1)

At −40° C. a solution of Lithium bis(trimethylsilyl)amide (9.72 mL, 9.72mmol) was added dropwise to a solution of piperidine-2,6-dione 9-1 (500

mg, 4.42 mmol) in THF (20 mL). After 15 minutes at −40° C., the mixturewas allowed to warmed and the mixture was stirred at RT for 4h. TLC (50%ethyl acetate in hexane, Rf=0.5) showed completion of the reaction. Itwas quenched with a saturated solution of ammonium chloride and theaqueous phase was extracted with dichloromethane (5×50 ml). The combinedorganic phases were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyusing ethyl acetate in hexane (30%) to provide tert-butyl2-(2,6-dioxopiperidin-3-yl)acetate 13-1 (450 mg, 1.98 mmol, 45.0%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.67 (brs, 1H), 2.83-2.78(m, 1H), 2.64-2.59 (m, 1H), 2.50-2.43 (m, 3H), 1.84-1.76 (m, 2H), 1.39(s, 9H)

Synthesis of (2,6-Dioxo-piperidin-3-yl)-acetic acid (13-2)

To a DCM solution (9 mL) of 13-1 (520 mg, 2.28 mmol) at 0° C. was addedTFA (3.48 mL, 45.6 mmol) and the resulting solution was warmed to roomtemperature and stirred for another 3 hours. The reaction mixture wasconcentrated under reduced pressure and the resultant solid wastriturated with Diethyl ether to afford 13-2 (360 mg, 2.10 mmol, 92%) asan off-white solid.

Synthesis of 2-(2,6-Dioxo-piperidin-3-yl)-N-(2-fluoro-phenyl)-acetamide(Compound 23)

To a stirred solution of 13-2 (70.0 mg, 408 μmol) in DMF (1 mL) wasadded 13-3 (45.3 mg, 408 μmol), DIPEA (300 μL, 1.63 mmol) and HATU (232mg, 612 μmol). The resulting mixture was stirred at room temperature for16 hours. The reaction mass was diluted with Ethyl acetate, washed withaqueous saturated NaHCO₃ solution, water and brine. The organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressure.The crude mass was purified over preparative TLC Plate (eluting with 2%MeOH in DCM) to afford Compound 23 (25.0 mg, 94.6 μmol, 23%) as whitesolid. ¹H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.78 (s, 1H), 7.87 (s,1H), 7.25-7.23 (m, 1H), 7.18-7.11 (m, 2H), 2.93-7.87 (m, 2H), 2.65-2.50(m, 2H), 1.93-1.90 (m, 1H), 1.82-1.80 (m, 1H).

Synthesis of 3-Prop-2-ynyl-piperidine-2,6-dione (14-1)

At −40° C. a solution of Lithium bis(trimethylsilyl)amide (38.7 mL, 38.7mmol) was added dropwise to a solution of piperidine-2,6-dione 9-1 (200

mg, 17.6 mmol). 3-bromoprop-1-yne (4.70 mL, 52.8 mmol) was then addedimmediately. After 15 minutes at −40° C., the mixture was allowed towarm to rt and the mixture was stirred for 4h. TLC (50% ethyl acetate inhexane, Rf=0.5) showed completion of the reaction. The reaction wasquenched with a saturated solution of ammonium chloride and the aqueousphase was extracted with dichloromethane (5×50 ml). The combined organicphases were dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography usingethyl acetate in hexane (30%) to provide3-(prop-2-yn-1-yl)piperidine-2,6-dione 14-1 (910 mg, 6.02 mmol, 34.2%)as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.73 (brs, 1H), 2.86(s, 1H), 2.68-2.54 (m, 4H), 2.43-2.40 (m, 1H), 2.1-2.00 (m, 1H),1.82-1.77 (m, 1H)

Synthesis of3-(1-Phenyl-1H-[1,2,3]triazol-4-ylmethyl)-piperidine-2,6-dione (Compound24)

14-1 (200.0 mg, 1.32 mmol) and 14-2 (314 mg, 2.64 mmol) were dissolvedin DMF-Water (1:1, 10 mL). The resulting solution was degassed withArgon for about 10 minutes and then CuSO₄.5H₂O (329 mg, 1.32 mmol) andNa-ascorbate (261 mg, 1.32 mmol) were added. The reaction mixture washeated at 110° C. for 16 hours to produce. The reaction was then cooledto room temperature and filtered through a short bed of celite. Thefiltrate was diluted with Ethyl acetate and washed with water and brine.The organic layer was dried over anhydrous Na₂SO₄ and then concentratedunder reduced pressure. The crude mass was purified over a preparativeTLC plate (eluting with 60% Ethyl acetate in Hexane) to afford Compound24 (34.7 mg, 128 μmol, 10%) as off white solid. ¹H NMR (400 MHz,DMSO-d6) δ 10.72 (s, 1H), 8.59 (s, 1H), 7.87 (d, J=7.9 Hz, 2H), 7.59 (t,J=7.8 Hz, 2H), 7.47 (t, J=7.4 Hz, 1H), 3.32-3.31 (m, 2H), 2.95-2.79 (m,2H), 2.59-2.50 (m, 1H), 1.94-1.91 (m, 1H), 1.75-1.72 (m, 1H); LC MS: ES+271.3.

Synthesis of3-(1-Methyl-1H-[1,2,3]triazol-4-ylmethyl)-piperidine-2,6-dione (Compound25)

A solution of sodium azide (429 mg, 6.60 mmol), Copper Sulfate (65.9 mg,264 μmol) and sodium ascorbate (130 mg, 660

mol) in DMF:H₂O (6 mL) was stirred for 5 minutes at room temperature. Tothis solution was added a solution of3-(prop-2-yn-1-yl)piperidine-2,6-dione 14-1 (0.2 g, 1.32 mmol) in DMF(1.0 mL) and iodomethane (281 mg, 1.98 mmol). The reaction mixture washeated in sealed tube for 16 hrs at 120° C. TLC showed completeconsumption of the starting material and formation of the desired spotat rf=0.3 in 50% ethylacetate-hexane. The solution was cooled anddiluted with EtOAc and then washed with water and brine solution. Theorganic and aqueous fractions were separated. The organic fraction wasthen dried over anhydrous sodium sulphate and evaporated under reducedpressure. The crude material was purified by flash chromatography toafford 3-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)piperidine-2,6-dione(Compound 25) (8.00 mg, 38.4 μmol, 3.0% yield). ¹H NMR (400 MHz,DMSO-d6) δ 10.68 (s, 1H), 7.80 (s, 1H), 3.98 (s, 3H), 3.17-3.14 (m, 1H),2.77-2.72 (m, 2H), 2.42 (m, 1H), 1.84-1.81 (m, 1H), 1.65-1.62 (m, 1H);LC MS: ES+ 209.2.

Synthesis of of 2,6-Bis-benzyloxy-3-ethynyl-pyridine (16-2)

A sealed tube was charged with 16-1 (1.0 g. 2.70 mmol), Et₃N (4.89 mL,35.1 mmol) and Ethynyltrimethylsilane (4.85 mL, 35.1 mmol) and theresulting solution was degassed with Argon for about 10 minutes followedby the addition of CuI (514 mg, 2.70 mmol) and PdCl₂(PPh3)₂ (1.89 g,2.70 mmol). The reaction tube was sealed and heated at 90° C. for 16hours. The reaction was then cooled to room temperature and filteredthrough a short bed of celite. The filtrate was partitioned betweenheptane and water. The organic layer was separated, dried over anhydrousNa₂SO₄ and concentrated. The crude mass was dissolved in MeOH (10 mL)and to it was added K₂CO₃ (713 mg, 5.16 mmol) and the solution wasstirred at ambient temperature for 2 hours to produce 16-2. The reactionmass was filtered through a short bed of celite and the filtrate wasconcentrated under reduced pressure. The crude mass was purified bycolumn chromatography (silica, gradient: 0-10% Ethyl acetate in Hexane)to afford 16-2 (462 mg, 1.46 mmol. 54%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 7.63 (d, J=8.24 Hz, 1H), 7.43-7.28 (m, 10H), 7.34 (d,J=8.16 Hz, 1H), 5.44 (s, 2H), 5.29 (s, 2H), 3.24 (s, 1H).

Synthesis of2,6-Bis-benzyloxy-3-(1-methyl-1H-[1,2,3]triazol-4-yl)-pyridine (16-3)

To a stirred mixture of NaN₃ (616 mg. 9.48 mmol), CuSO₄.5H₂O (78.9 mg.316 μmol) and Na-ascorbate (156 mg. 790 μmol) in DMF-water (1:1, 18 mL)was added 16-2 (500.0 mg, 1.58 mmol) and MeI (156 μL, 2.52 mmol) and theresulting mixture was stirred at 120° C. for 16 hours to produce 16-3.The reaction was then cooled to room temperature, diluted with Ethylacetate and filtered through a short bed of celite. The filtrate waswashed with water, brine, and dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude mass was purified bycolumn chromatography (silica, gradient: 0-25% Ethyl acetate in Hexane)to afford 16-3 (372 mg, 0.9995 mmol, 63.2%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.53 (d, J=8.20 Hz, 1H), 7.82 (s, 1H), 7.43-7.28(m, 10H), 6.53 (d, J=8.20 Hz, 1H), 5.48 (s, 2H), 5.35 (s, 2H), 4.06 (s,3H); LC MS: ES+ 372.8.

Synthesis of 3-(1-Methyl-1H-[1,2,3]triazol-4-yl)-piperidine-2,6-dione(Compound 26)

A 25 mL round bottom flask was charged with2,6-bis(benzyloxy)-3-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine 16-3 (150mg, 402 μmol) and ethanol (10.0 mL). The solution was degassed for 15minutes under argon atmosphere. To the solution was added palladium oncarbon (10 wt %, 64.0 mg, 602 μmol) and the reaction was continued for 2hrs under a hydrogen balloon. TLC showed complete consumption of thestarting material and formation of the desired spot at rf=0.2 inethylacetate. The reaction mixture was filtered over a celite bed andthe filtrate was evaporated under reduced pressure. The crude residuewhich was purified by combiflash chromatography to

provide 3-(1-methyl-1H-1,2,3-triazol-4-yl)piperidine-2,6-dione Compound26 (35.0 mg, 180 μmol, 44.8%) as a white solid. ¹H NMR (400 MHz,DMSO-d6) δ 10.86 (s, 1H), 7.98 (s, 1H), 3.32 (s, 4H), 2.66 (dt, J=16.4,7.7 Hz, 1H), 2.56 (d, J=5.0 Hz, 1H), 2.17 (q, J=5.6 Hz, 2H); ¹H NMR (400MHz, Chloroform-d) δ 7.86 (s, 1H), 7.63 (s, 1H), 4.10 (s, 3H), 3.98 (dd,J=9.2, 5.2 Hz, 1H), 2.89 (dt, J=17.7, 5.6 Hz, 1H), 2.68 (ddd, J=17.8,9.8, 5.1 Hz, 1H), 2.60-2.48 (m, 1H), 2.43 (dtd, J=14.1, 9.4, 4.8 Hz,1H); LC MS: ES+ 195.0.

Synthesis of2,6-Bis-benzyloxy-3-(1-phenyl-1H-[1,2,3]triazol-4-yl)-pyridine (17-1)

To a stirred mixture of Azidobenzene 14-2 (150 mg, 1.26 mmol),CuSO₄.5H₂O (31.3 mg, 126 μmol) and Na-ascorbate (62.7 mg, 317 μmol) inDMF-water (1.1, 6 mL) was added 16-2 (200 mg, 634 μmol) and theresulting mixture was stirred at 120° C. for 16 h. The reaction was thencooled to room temperature, diluted with Ethyl acetate and filteredthrough a short bed of celite. The filtrate was washed with water,brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude mass was purified by column chromatography (silica,gradient: 0-10% Ethyl acetate in Hexane) to afford 17-1 (46.2 mg. 106μmol, 17%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (d, J=8.24Hz, 1H), 8.31 (s, 1H), 7.68 (d, J=7.68), 7.51-7.30 (m, 13H), 6.57 (d,J=8.28 Hz, 1H), 5.51 (s, 2H), 5.38 (s, 2H).

Synthesis of 3-(1-Phenyl-1H-[1,2,3]triazol-4-yl)-piperidine-2,6-dione(Compound 27)

A 25 mL rbf was charged with2,6-bis(benzyloxy)-3-(1-phenyl-1H-1,2,3-triazol-4-yl)pyridine 17-1(200.0 mg, 460 μmol) and ethanol (10.0 mL) and the solution was degassedfor 15 minutes under an argon atmosphere. To the reaction was addedpalladium on carbon (48.9 mg, 460 μmol) and stirring was continued for 2hrs in presence of a hydrogen balloon. TLC showed complete consumptionof the starting material and the formation of the desired spot at rf=0.2in 100% ethylacetate. The reaction mixture was filtered over a celitebed and the filtrate was evaporated under reduced pressure to obtain thecrude which was purified by combiflash chromatography to obtain thedesired compound which was further purified by a preparative TLC (60%ethylacetate-Hexane) to afford3-(1-phenyl-1H-1,2,3-triazol-4-yl)piperidine-2,6-dione (Compound 27)(8.40 mg, 32.7 μmol, 7.17%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.75 (s, 1H), 7.90 (d, J=7.9Hz, 2H), 7.60 (t, J=7.7 Hz, 2H), 7.49 (t, J=7.3 Hz, 1H), 4.16 (t, J=7.9Hz, 1H), 2.74-2.59 (m, 2H), 2.33-2.24 (m, 2H); LC MS: ES+ 257.2.

Synthesis of N-Pyridin-2-ylmethyl-malonamic acid ethyl ester (18-2)

To a DMF solution (20 mL) of 18-1 (1 g, 9.24 mmol) was added Monoethylmalonic acid (1.22 g, 9.24 mmol), DIPEA (4.82 mL, 27.7 mmol) and HATU(6.99 g, 18.4 mmol). The resulting solution was stirred at ambienttemperature for 16 hours. The reaction mixture was diluted with Ethylacetate, washed with water and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crude masswas purified by column chromatography (slica, gradient: 0-25% Ethylacetate in Hexane) to afford 18-2 (540 mg, 2.42 mmol, 26%) as anoff-white solid. LC MS: ES+ 223.2.

Synthesis of Imidazo[1,5-a]pyridin-3-yl-acetic acid ethyl ester (18-3)

18-2 (540 mg, 2.42 mmol) was taken up in POCl₃ (5 mL) and stirred atreflux for 16 h. The volatiles were removed under reduce pressure andthe residue was taken up in aqueous saturated NaHCO₃ solution and thenextracted with DCM. The combined extracts were dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude mass waspurified by column chromatography (silica, gradient: 0-2% MeOH in DCM)to afford 18-3 (260 mg, 1.27 mmol, 52.6%) as an off-brown gum. LC MS:ES+ 205.2.

Synthesis of 4-Cyano-2-imidazo[1,5-a]pyridin-3-yl-butyric acid ethylester (18-4)

Lithium diisopropylamide (1.02 mL, 2.04 mmol) was added dropwise to aTHF solution (10 mL) of 18-3 (250 mg, 1.02 mmol) at −78° C. Theresulting solution was stirred at 0° C. for 1 hour. The reaction wasagain cooled to −78° C. and 3-Bromopropionitrile (84.2 μL, 1.02 mmol)was added and stirred was continued for 30 minutes. The reaction wasthen gradually warmed to room temperature and stirring was continued foranother 3 hours. The reaction mixture was quenched with aqueoussaturated NH₄Cl solution, extracted with Ethyl acetate, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford 18-4(175 mg, 680 μmol, 67%) crude as a brown gum. LC MS: ES+ 257.8.

Synthesis of 3-Imidazo[1,5-a]pyridin-3-yl-piperidine-2,6-dione (Compound28)

18-4 (175 mg, 680 μmol) was taken up into a mixture of conc. H₂SO₄ (0.5mL) and Acetic acid (2.5 mL) and the resulting solution was then heatedat 110° C. for 6 hours. The reaction mixture was cooled to roomtemperature, poured onto an ice cold solution of aqueous NaHCO₃ and thenextracted with Ethyl acetate. The combined extracts were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crude masswas purified by column chromatography (silica, gradient: 0-50% Ethylacetate in Hexane) to afford Compound 28 (6.20 mg, 27.0 μmol, 4%) asbrown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.23 (d, J=7.3Hz, 1H), 7.54 (d, J=9.1 Hz, 1H), 7.33 (s, 1H), 6.77 (t, J=6.7 Hz, 1H),6.67 (t, J=6.8 Hz, 1H), 4.63 (dd, J=10.4, 5.0 Hz, 1H), 2.70-2.63 (m,2H), 2.25-2.17 (m, 2H); LC MS: ES+ 230.2.

Synthesis of methyl 2-(1-methyl-1H-indol-3-yl)acetate (19-2)

To a stirred solution of 2-(1H-indol-3-yl)acetic acid (19-1) (3.0 g,17.1 mmol) in DMF (20.0 mL) was added K₂CO₃ (7.09 g, 51.3 mmol) and thereaction mixture was stirred for 15 minutes. Methyl iodide (3.19 mL,51.3 mmol) was then added to the reaction mixture and stirring wascontinued at room temperature for 16 hours. TLC showed formation of anew spot (Rf-0.5 in 20% ethyl acetate/hexane). The reaction was dilutedwith water and extracted with ethyl acetate. The organic layer waswashed with water, brine, dried over sodium sulfate and concentrated.¹HNMR and LCMS showed only the acid group was converted to its methylester, N-methylation didn't took place. The residue was again dissolvedin THF (15.0 mL) and to it was added NaH (1.0 eq) at 0° C. MeI (1.0 eq)was then added to the reaction mixture and the reaction mixture wasstirred at room temperature for 3 hours. TLC showed a new spot formation(Rf-0.6 in 10% ethyl acetate/hexane). The reaction was diluted with coldwater and ethyl acetate. The organic layer was separated and washed withwater, brine, dried over sodium sulfate, concentrated and the resultingresidue was purified by column chromatography (silica 100-200, 0%-2%ethyl acetate/hexane) to afford methyl 2-(1-methyl-1H-indol-3-yl)acetate19-2 (1.40 g, 6.88 mmol, 40.3%) as a yellow oil. LC MS: ES+ 204.3.

Synthesis of 4-Cyano-2-(1-methyl-1H-indol-3-yl)-butyric acid methylester (19-3)

19-2 (500 mg, 2.46 mmol) was dissolved in 1,4-Dioxane (5 mL) and to thissolution was added Benzyltrimethylammonium hydroxide (55.6 μL, 123 μmol)and Acrylonitrile (160 μL, 2.46 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 16 hours and then diluted with water andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude mass was purified by column chromatography (silica,gradient: 0-20% Ethyl acetate in Hexane) to afford 19-3 (145 mg, 565μmol, 23%) as a brown solid. LC MS: ES+ 310.2.

Synthesis of 4-Cyano-2-(1-methyl-1H-indol-3-yl)-butyric acid (19-4)

19-3 (140 mg, 546 μmol) was dissolved in a mixture of THF (3 mL), water(1 mL) and methanol (0.5 mL) and to this solution was added lithiumhydroxide monohydrate (34.3 mg, 818 μmol). The reaction mixture wasstirred at room temperature for 4 hours. The solvent was evaporated andthe residue was acidified with 1N HCl. The solution was extracted withethyl acetate and the organic layer was washed with brine, dried Na₂SO₄and evaporated to afford 19-4 (94.0 mg, 387 μmol, 71%) as a gummy solid.LC MS: ES+ 243.1.

Synthesis of 3-(1-Methyl-1H-indol-3-yl)-piperidine-2,6-dione (Compound29)

To a suspension of 19-4 (90 mg, 371 μmol) in Toluene (1 mL) was addedsulfuric acid (3.95 μL, 74.2 μmol) at 0° C. The reaction mixture wasstirred at 100° C. for 16 hours. The reaction was then basified with aq.NaHCO₃ and extracted with ethyl acetate. The organic layer was washedwith brine, dried over Na₂SO₄ and evaporated under reduced pressure. Thecrude residue was purified by preparative TLC (3%methanol-dichloromethane) to afford Compound 29 (45.0 mg, 185 μmol, 50%)as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.49(d, J=7.9 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.22-7.10 (m, 2H), 7.01 (t,J=7.4 Hz, 1H), 4.09 (dd, J=10.4, 4.9 Hz, 1H), 3.75 (s, 3H), 2.68 (td,J=11.2, 10.5, 5.6 Hz, 1H), 2.56 (d, J=4.9 Hz, 1H), 2.22 (dd, J=12.5, 8.2Hz, 1H), 2.11 (dd, J=13.4, 5.7 Hz, 1H); LC MS: ES+ 243.4.

To a stirred solution of 20-1 (2.0 g, 9.24 mmol) in DMF (15.0 mL) wasadded K₂CO₃ (2.54 g, 18.4 mmol) and the reaction mixture was stirred atroom temperature for 15 minutes. Methyl iodide (855 μL, 13.8 mmol) wasadded and the reaction mixture was stirred for 4 hours. TLC showedformation of two new spots. The reaction mixture was diluted with ethylacetate and water. The layers were separated and the organic layer waswashed with water, brine, and dried over sodium sulfate. The solutionwas concentrated and the crude material was purified by columnchromatography (silica, 100-200, gradient 0%-30% ethyl acetate/hexane)to afford 20-2 (400 mg, 1.73 mmol, 19%) and 20-3 (1.8 g, 7.81 mmol, 85%)as colorless oils. ¹H NMR (20-2, polar fraction) (400 MHz, CDCl₃) δ;7.47-7.39 (m, 5H), 6.84 (s, 1H), 4.42 (q, J=14.04, 7.0 Hz, 2H), 3.94 (s,3H), 1.40 (t, J=7.08 Hz, 3H). ¹H NMR (20-3, non-polar fraction) (400MHz, CDCl₃) δ; 7.78 (d, J=7.4 Hz, 2H), 7.39 (t, J=7.24 Hz, 2H),7.32-7.29 (m, 1H), 7.11 (s, 1H), 4.36 (q, J=14.16, 7.08 Hz, 2H), 4.22(s, 3H), 1.39 (t, J=7.0 Hz, 3H)

Synthesis of (1-methyl-5-phenyl-1H-pyrazol-3-yl)-methanol (21-1)

To a stirred solution of CaCl₂ (116 mg, 1.05 mmol) in THF (5.0 mL) wasadded NaBH₄ (79.8 mg, 2.11 mmol) and the mixture was stirred at roomtemperature for 1 hour. A solution of 20-2 (325.0 mg, 1.41 mmol) in THF(5.0 mL) was then added to the reaction mixture and the reaction mixturewas subjected to reflux for 24 hours. The reaction was cooled anddiluted with ice-water and ethyl acetate. The layers were separated andorganic layer was washed with water, brine, dried over sodium sulfate,concentrated and the crude material was purified by columnchromatography using (silica, 100-200, 0%-25% ethyl acetate/hexane) toafford 21-1 (250 mg, 1.32 mmol, 94%) as a white solid. LC MS: ES+ 189.0.

Synthesis of 3-chloromethyl-1-methyl-5-phenyl-1H-pyrazole (21-2)

To a stirred solution of 21-1 (570.0 mg, 3.02 mmol) in DCM (10.0 mL) wasadded triethyl amine (848 μL, 6.04 mmol), followed by mesyl chloride(350 μL, 4.53 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 16 hours and then diluted with DCM, washed withsaturated aqueous NaHCO₃ solution, water, brine, dried over sodiumsulfate and concentrated to afford 21-2 (624 mg, 3.01 mmol, 100%) as abrown gum. This material was used in the next step without anypurification. LC MS: ES+ 206.8.

Synthesis of (1-methyl-5-phenyl-1H-pyrazol-3-yl)-acetonitrile (21-3)

To a stirred solution of 21-2 (624.0 mg, 3.01 mmol) in DMF (5.0 mL) wasadded NaCN (176 mg, 3.61 mmol) and the reaction mixture was heated at60° C. for 16 hours. The reaction was diluted with water and ethylacetate. The organic layer was separated and washed with water, brine,dried over sodium sulfate, concentrated and the crude mass was purifiedby column chromatography (0-25% ethyl acetate/hexane) to afford 21-3(500 mg, 2.53 mmol, 84%) as a brown gum. LC MS: ES+ 198.2.

Synthesis of 4-cyano-4-(1-methyl-5-phenyl-1H-pyrazol-3-yl)-butyric acidethyl ester (21-4)

A 25 ml two-neck round bottom flash was charged with 21-3 (300.0 mg,1.52 mmol) in Tetrahydrofuran (10 mL) under argon and cooled to −78° C.Lithium diisopropylamide (1.52 mL, 3.04 mmol) was added to the reactionmixture dropwise while allowing the temperature to increase from −78° C.to room temperature over 1h. The reaction was again cooled to −78° C.and ethyl 3-bromopropanoate (194 μL, 1.52 mmol) was added to thereaction mixture. The reaction was gradually warmed to room temperatureand stirring was continued for 3 hours. The reaction was quenched withsaturated ammonium chloride solution, extracted with ethyl acetate,dried over sodium sulfate and concentrated under reduced pressure toobtain the crude which was purified by column chromatography (silica,gradient: 0-20% Ethyl acetate in Hexane) to afford 21-4 (56.3 mg, 189μmol, 12%) as a yellow gum. LC MS: ES+ 298.2.

Synthesis of 4-cyano-4-(1-methyl-5-phenyl-1H-pyrazol-3-yl)-butyric acid(21-5)

To a 25 mL round bottom flask was added 21-4 (230.0 mg, 773 μmol) andTHF: H₂O (5 mL) and the solution was cooled. To the solution was addedlithium hydroxide monohydrate (32.4 mg, 773 μmol) and the reaction wasstirred at room temperature for 2.5 hrs. The solvent was firstevaporated under reduced pressure, then water and ethyl acetate wasadded and the organic and aqueous fractions were separated. The aqueousfraction was then acidified with 2N HCl to pH 3 and the desired compoundwas then extracted with ethyl acetate, washed with water and dried overanhydrous sodium sulfate and evaporated under reduced pressure to obtain21-5 (46.1 mg, 171 μmol, 22%) as an off white solid. LC MS: ES+ 270.1.

Synthesis of 3-(1-methyl-5-phenyl-1H-pyrazol-3-yl)-piperidine-2,6-dione(Compound 30)

To a 10 mL round bottom flask was added4-cyano-4-(1-methyl-5-phenyl-1H-pyrazol-3-yl)butanoic acid 21-5 (54.0mg, 200 μmol) followed by the addition of toluene (2.0 mL) and sulphuricacid (10.6 μL, 200 μmol) and the reaction was refluxed at 110° C. for 7hrs. TLC showed complete consumption of the starting material andformation of the desired spot at if 0.4 in 5% MeOH-DCM. The reactionmixture was diluted with ethylacetate, washed with sodium bicarbonatesolution, water, brine solution and the organic and aqueous fractionswere separated. The organic fraction was then dried over anhydroussodium sulphate and evaporated under reduced pressure to obtain thedesired compound which was then washed with ether and pentane to obtain3-(1-methyl-5-phenyl-1H-pyrazol-3-yl)piperidine-2,6-dione Compound 30(25.0 mg, 92.8 μmol, 46.4%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.79 (s, 1H), 7.56-7.45 (m, 4H), 7.48-7.39 (m, 1H), 6.33 (s,1H), 3.88 (t, J=6.9 Hz, 1H), 3.81 (s, 3H), 2.58 (td, J=6.4, 6.0, 2.9 Hz,2H), 2.16 (q, J=6.7 Hz, 2H); LC MS: ES+ 270.3.

To a stirred solution of4-cyano-4-(1-methyl-3-phenyl-1H-pyrazol-5-yl)butanoic acid (22-1,prepared from 20-3 by the general procedures in Scheme 21) (35 mg, 129μmol) in Toluene (2.0 mL) was added H₂SO₄ (7.50 μL, 141 μmol) and thereaction mixture was heated at 100° C. for 5 hours. TLC showed formationof a new spot (Rf-0.4 in 5% MeOH/DCM). The reaction was diluted withsaturated aqueous NaHCO₃ and ethyl acetate. The organic layer wasseparated and washed with water and brine, dried over sodium sulfate andthen concentrated. The resultant solid was triturated with pentane to

afford 3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)piperidine-2,6-dione(Compound 31) (15.0 mg, 55.7 μmol, 43.2%) as an off-white solid. ¹H NMR(400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.38 (t,J=7.5 Hz, 2H), 7.32-7.22 (m, 2H), 6.60 (s, 1H), 4.22 (dd, J=12.3, 4.8Hz, 1H), 3.81 (s, 3H), 2.72 (ddd, J=17.6, 12.4, 5.4 Hz, 1H), 2.61 (dt,J=17.3, 4.1 Hz, 1H), 2.31 (qd, J=12.7, 4.6 Hz, 1H), 2.16 (dt, J=13.0,4.4 Hz, 1H); LC MS: ES+ 270.3.

Synthesis of 2,6-bis(benzyloxy)-3-(o-tolyl)pyridine (23-2)

A stirred mixture of 16-1 (170 mg, 459 μmol), 23-1 (124.8 mg 918 μmol)and Potassium phosphate (211 mg, 918 μmol) in Dioxane:water (6:1, 7 mL)was degassed with argon for 10 minutes. PdCl₂dppf.DCM (38 mg, 45.9 μmol)was added and stirred the reaction was stirred at 110° C. for 16 hours,cooled to room temperature and then filtered through a short bed ofcelite. The filtrate was diluted with Ethyl acetate, washed with water,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude mass was purified by column chromatography (silica, gradient: 0-5%Ethyl acetate in Hexane) to afford 23-2 (160 mg, 419 μmol, 91%) as asticky solid. LC MS: ES+ 382.2.

Synthesis of 3-(o-tolyl)piperidine-2,6-dione (Compound 32)

To a solution of 2,6-bis(benzyloxy)-3-(o-tolyl)pyridine (23-2) (200 mg,524 μmol) in EtOH (10 mL) under inert atmosphere was added Pd/C (60 mg,563 μmol) and reaction mixture was stirred at room temperature underhydrogen atmosphere overnight. Reaction progress was monitored by TLCand LC-MS. Upon completion, the reaction mixture was filtered throughcelite bed and the mother liquor was evaporated to dryness. The crudematerial was submitted for preparative HPLC to yield3-(o-tolyl)piperidine-2,6-dione (Compound 32) (40.0 mg, 196 μmol, 38%)as a violet solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.93 (d,J=7.9 Hz, 1H), 7.48 (d, J=3.4 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.45 (d,J=3.5 Hz, 1H), 4.07 (dd, J=9.2, 5.2 Hz, 1H), 3.76 (s, 3H), 2.63 (t,J=6.5 Hz, 2H), 2.41-2.27 (m, 1H), 2.24-2.11 (m, 1H).

Synthesis of 2,6-bis(benzyloxy)-3-(1-methyl-1H-pyrazol-3-yl)pyridine(24-2)

To a stirred solution of 2,6-bis(benzyloxy)-3-bromopyridine (16-1) (177mg, 480 μmol),1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole24-1 (100.0 mg, 480 μmol) and potassium phosphate (221 mg, 960 μmol) inwater: dioxane (10 mL) was degassed with argon for 10 minute.PdCl₂(dppf)-DCM (39.1 mg, 48.0 μmol) was added to above reaction mixtureand the solution was again purged with argon and refluxed for 16 hour at100° C. After completion of the reaction was observed by TLC (Rf=0.5 in30% EtOH/Hexane), the reaction mixture was filtered through celite andconcentrated. The residue was again dissolved in EtOAc (50 mL), washedwith water, brine and evaporated. The crude residue was purified bycombi flash chromatography (4 g Isco gold, hexane/EtOAc 70-30%) to give2,6-bis(benzyloxy)-3-(1-methyl-1H-pyrazol-3-yl)pyridine 24-2 (120 mg,323 μmol, 67.4%) as a white gummy solid. ¹H NMR (400 MHz, DMSO-d6) δ8.17 (d, J=8.2 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.46-7.42 (m, 4H),7.39-7.33 (m, 4H), 7.33-7.31 (m, 2H), 6.61 (d, J=2.1 Hz, 1H), 6.51-6.49(m, 1H), 5.46 (s, 2H), 5.37 (s, 2H), 3.85 (s, 3H).

Synthesis of 3-(1-methyl-1H-pyrazol-3-yl)piperidine-2,6-dione (Compound33)

To a stirred solution of2,6-bis(benzyloxy)-3-(1-methyl-1H-pyrazol-3-yl)pyridine 24-2 (120 mg,323 μmol) in ethanol (5 mL) added Pd on C (10 wt %, 342 mg, 1.61 mmol)and the solution was purged with argon for 10 minutes. After that ahydrogen gas balloon was added to the vessel and reaction mixture wasstirred at rt for 6 hours. TLC showed an new spot formed (Rf-0.3 in 5%MeOH/DCM) and starting was fully consumed. The reaction mixture wasfiltered through a celite bed and evaporated. The product was purifiedby washing with pentane to give3-(1-methyl-1H-pyrazol-3-yl)piperidine-2,6-dione (Compound 33) (60.0 mg,310 μmol, 96.1%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.75 (s, 1H), 7.60 (d, J=2.2 Hz, 1H), 6.12 (d, J=2.2 Hz, 1H), 3.83-3.80(m, 1H), 3.78 (s, 3H), 2.56-2.54 (m, 2H), 2.10-2.09 (m, 2H); LC MS: ES+194.2.

To a stirred solution of 16-1 (5.0 g, 13.5 mmol) in Dioxane (20 mL) wasadded 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.12g, 20.2 mmol) and KOAc (2.64 g, 27.0 mmol). The reaction mixture wasdegassed with argon for 10 minutes. PdCl2(dppf).DCM (1.10 g, 1.35 mmol)was added and the resulting mixture was stirred at 100° C. for 16 hours.The reaction was then cooled to room temperature and filtered through ashort bed of celite. The filtrate was diluted with Ethyl acetate, washedwith water, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude mass was purified by column chromatography (silica,gradient: 0-5% Ethyl acetate in Hexane) to afford 25-1 (3.5 g, 62%) as apale yellow solid.

Synthesis of 2′,6′-bis(benzyloxy)-6-methoxy-2,3′-bipyridine (26-2)

A stirred solution of 2-bromo-6-methoxypyridine 26-1 (150 mg, 797 μmol),2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine25-1 (496 mg, 1.19 mmol) and Potassium phosphate (366 mg, 1.59 mmol) inwater: dioxane (10 mL) was degassed with argon for 10 minutes.PdCl2dppf.DCM (65.0 mg, 79.7 μmol) was added to above reaction mixtureand the solution was again purged with argon and refluxed for 16 hoursat 100° C. Upon completion of reaction as monitored by TLC (Rf=0.5 in20% EtOH/Hexane), the reaction mixture was filtered through celite andthe filtrate was evaporated to dryness. The residue was again dissolvedin EtOAc (50 mL), washed with water and brine and evaporated. Theproduct was purified by combi flash chromatography (4 g Isco gold,hexane/EtOAc 80-20%) to give2′,6′-bis(benzyloxy)-6-methoxy-2,3′-bipyridine (26-2) (125 mg, 313 μmol,39.4%) as a white gummy solid. LC MS: ES+ 393.3.

Synthesis of 3-(6-methoxypyridin-2-yl)piperidine-2,6-dione (Compound 34)

To a stirred solution of 2′,6′-bis(benzyloxy)-6-methoxy-2,3′-bipyridine(26-2) (120 mg, 301 μmol) in ethanol (7 mL) was added Pd—C (10 wt %,31.9 mg, 301 μmol) and the reaction was purged with argon for 10minutes. After that a hydrogen gas balloon was added and reactionmixture stirred at rt for 3 hours. TLC showed that new spots were formed(Rf-0.3 in 5% MeOH/DCM) and the starting material was fully consumed.The reaction mixture was filtered through a celite bed and the filtratewas evaporated. The product was purified by silica gel flashchromatography (4 g Isco gold, DCM/MeOH 0-10%) followed by prep HPLCpurification to obtained 3-(6-methoxypyridin-2-yl)piperidine-2,6-dione(Compound 34) (14.0 mg, 63.5 μmol, 21.1%) as a white solid. ¹H NMR (400MHz, DMSO-d6) δ 10.85 (s, 1H), 7.68 (t, J=7.8 Hz, 1H), 6.94 (d, J=7.2Hz, 1H), 6.72 (d, J=8.2 Hz, 1H), 3.93 (dd, J=8.6, 5.3 Hz, 1H), 3.78 (s,3H), 2.58 (d, J=6.6 Hz, 2H), 2.23-2.11 (m, 2H); LC MS: ES+ 221.2.

Synthesis of6-(2,6-Bis-benzyloxy-pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine(27-2)

To a stirred solution of 6-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine(27-1) (500.0 mg, 2.36 mmol) and2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine25-1 (1.18 g, 2.82 mmol) in a sealed tube in dioxane (5 mL) and water(1.5 mL) was added K₃PO₄ (1.08 g, 4.69 mmol) and it was degassed for 10min and then PdCl₂(dppf)-DCM (0.2 g, 244 μmol) and again degassed for 5min. After degassing was complete, the sealed tube was closed with ateflon cap and reaction mixture was stirred at 80° C. for 16 h. Afterreaction completion as checked by TLC, the reaction mixture was filteredthrough celite and the organic layer was diluted with ethyl acetate,washed with water and brine, and the organics were dried over anhydroussodium sulphate, filtered and concentrated under reduced pressure. Thecrude residue was purified by column chromatography eluted with 0 to 20%ethyl acetate in hexane to provide6-(2,6-Bis-benzyloxy-pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine(27-2) (300 mg, 711 umol, 30% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.36(d, J=8.2 Hz, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.51(d, J=3.4 Hz, 1H), 7.46-7.44 (m, 4H), 7.40-7.30 (m, 6H), 6.62 (d, J=8.2Hz, 1H), 6.44 (d, J=3.4 Hz, 1H), 5.50 (s, 2H), 5.41 (s, 2H), 3.84 (s,3H); LC MS: ES+ 422.4.

Synthesis of3-(1-Methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-piperidine-2,6-dione(Compound 35)

To a stirred solution of6-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine(27-2) (0.200 g, 474 μmol) in THF (20 mL) was added Pd/C (0.100 g, 943μmol). Hydrogen gas was bubbled through this solution at 1 atm, rt for 2h. After completion of the reaction, as checked by TLC, the reactionmixture was filtered through a celite bed and the organic layer wasconcentrated under reduced pressure. The crude compound which waspurified by prep HPLC to provide3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidine-2,6-dione (Compound35) (15.0 mg, 61.6 μmol, 13.0%) as a grey solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.83 (s, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.48 (d, J=3.4 Hz,1H), 7.05 (d, J=8.0 Hz, 1H), 6.45 (d, J=3.5 Hz, 1H), 4.07 (dd, J=9.2,5.2 Hz, 1H), 3.76 (s, 3H), 2.63 (t, J=6.5 Hz, 2H), 2.41-2.27 (m, 1H),2.24-2.11 (m, 1H); LC MS: ES+ 244.1.

Synthesis of4-(2,6-Bis-benzyloxy-pyridin-3-yl)-1-methyl-1H-benzoimidazole (28-2)

A stirred solution of 4-bromo-1-methyl-1H-benzo[d]imidazole (28-1) (100mg, 473 μmol)2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine25-1 (295 mg, 709 μmol) and Potassium phosphate (217 mg, 946 μmol) inwater: dioxane (10 mL) was degassed with argon for 10 minutes.PdCl₂(dppf)-DCM (38.6 mg, 47.3 μmol) was added and the solution wasagain purged with argon and then refluxed for 16 hours at 100° C. Aftercompletion of the reaction, as monitored by TLC (Rf=0.5 in 10%EtOH/Hexane), the reaction mixture was filtered through celite and thefiltrate was evaporated. The residue was again dissolved in EtOAc (50mL), washed with water and brine and evaporated to dryness. The crudewas purified by combi flash chromatography (12 g Isco gold, hexane/EtOAc95-5%) to give4-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole (28-2)(110 mg, 55.2%) as a white gummy solid. LC MS: ES+ 422.0.

Synthesis of3-(1-Methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-piperidine-2,6-dione(Compound 36)

To a stirred solution of4-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-benzo[d]imidazole (28-2)(110 mg, 260 μmol) in ethanol (5 mL) was added Pd—C (96.3 mg, 909 μmol)and the solution was purged with argon for 10 minutes. After thathydrogen gas (˜15 psi) passed through balloon, and reaction mixturestirred at rt for 6 hours. TLC showed a new spot formed (Rf-0.3 in 5%MeOH/DCM) and the starting material was fully consumed. The reactionmixture was filtered through a celite bed and the filtrate wasevaporated. The crude product was purified by washing with pentane togive 3-(1-methyl-1H-benzo[d]imidazol-4-yl)piperidine-2,6-dione (Compound36) (34.0 mg, 139 μmol, 53.7%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.82 (s, 1H), 8.13 (s, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.22 (t,J=7.7 Hz, 1H), 7.05 (d, J=7.3 Hz, 1H), 4.24 (d, J=10.2 Hz, 1H), 3.83 (s,3H), 2.74-2.67 (m, 1H), 2.56-2.50 (m, 2H), 2.04-2.03 (m, 1H). LC MS: ES+244.1.

Synthesis of 3-(2,6-Bis-benzyloxy-pyridin-3-yl)-1-methyl-1H-indazole(29-2)

To a stirred solution of 29-1 (160.0 mg, 620 μmol) in dioxane:water(4:1)(10.0 mL) was added 25-1 (388 mg, 930 μmol) and Cs₂CO₃ (606 mg,1.86 mmol) and the reaction mixture was degassed for 15 minutes.PdCl₂(dppf)-DCM (75.9 mg, 93.0 μmol) was added and the reaction mixturewas heated at 100° C. for 16 hours. The reaction was cooled, filteredthrough a celite bed, washed with ethyl acetate. The organic layer wasseparated, dried over sodium sulfate and concentrated. The crudematerial was purified by column chromatography using (silica, gradient:0-7% Ethyl acetate in Hexane) to afford 29-2 (220 mg, 521 μmol, 84%) asa colorless gum. LC MS: ES+ 422.1.

Synthesis of 3-(1-Methyl-1H-indazol-3-yl)-piperidine-2,6-dione (Compound37)

A stirred solution of 29-2 (220.0 mg, 521 μmol) in ethanol (10.0 mL) wasdegassed for 15 minutes. Then 10% Pd—C (55.4 mg, 521 μmol) was added tothe reaction mixture and the reaction mixture was subjected tohydrogenation under a hydrogen balloon for 4 hours. The reaction wasfiltered through a celite bed and the filtrate was concentrated. Thecrude material was purified by column chromatography using (silica,gradient: 0-1% Methanol in DCM) to afford Compound 37 (65.0 mg, 267μmol, 52%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s,1H), 7.72 (d, J=8.2 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.39 (t, J=7.4 Hz,1H), 7.12 (t, J=7.5 Hz, 1H), 4.38 (dd, J=9.8, 5.0 Hz, 1H), 4.00 (s, 3H),2.67-2.55 (m, 2H), 2.38 (ddd, J=13.9, 9.6, 4.9 Hz, 1H), 2.24-2.12 (m,1H); LC MS: ES+ 244.3.

Chiral Separation of Compound 37 to Provide Compound 38 and Compound 39:

Preparative Chiral HPLC was done using Waters auto purificationinstrument in normal phase. Column name: Chiralpak ID (250×20 mm, 5μ),Flow rate: 16.0 ml/min, Mobile phase: 100% Acetonitrile, Total runtime:15 min, Sample diluents: DCM+Acetonitrile. Elution order: Compound 38and then Compound 39.

Synthesis of3-(2,6-Bis-benzyloxy-pyridin-3-yl)-1-methyl-1H-quinolin-2-one (30-2)

A stirred solution of2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine25-1 (2.19 g, 5.25 mmol) and 3-bromo-1-methylquinolin-2(1H)-one (30-1)(500.0 mg, 2.10 mmol) in dioxane/water (30 mL) in a sealed tube wasdegassed for 10 minutes under argon atmosphere. PdCl₂(dppf)-DCM (153 mg,210 μmol) was added and the reaction then heated to 80° C. for 10 h. TLCwas checked in 30% ethyl acetate/hexane which showed the completeconsumption of starting material and formation of the desired spot at rf0.4 in 30% ethylacetate-hexane. The reaction mixture was diluted withethyl acetate and washed with water. The layers were separated and theorganic layer was concentrated under reduced pressure and purified usingcombiflash and the desired compound was eluted in 50% ethylacetate/hexane and concentrated to afford3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methylquinolin-2(1H)-one (30-2)(729 mg, 1.62 mmol, 77.4%) as an off-white solid. LC MS: ES+ 448.9.

Synthesis of3-(1-Methyl-2-oxo-1,2-dihydro-quinolin-3-yl)-piperidine-2,6-dione(Compound 40)

A 50 ml round bottom flask was charged with3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methylquinolin-2(1H)-one (30-2)(800.0 mg, 1.78 mmol) and ethanol (10 mL). The solution was degassed for15 minutes under argon atmosphere, palladium on charcoal (189 mg, 178μmol) was added and the reaction was continued for 2 hrs in the presenceof a hydrogen balloon. TLC was checked, which showed completeconsumption of starting material and formation of the desired spot at rf0.3 in 5% MeOH-DCM. The reaction mixture was filtered through a celitebed and evaporated under reduced pressure. The crude residue waspurified by flash chromatography to afford3-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)piperidine-2,6-dione(Compound 40) (14.0 mg, 51.7 μmol, 2.91%) as an off-white solid. ¹H NMR(400 MHz, DMSO-d6) δ 10.78 (s, 1H), 7.88 (s, 1H), 7.71 (d, J=7.48 Hz,1H), 7.64-7.60 (m, 1H), 7.53 (d, J=8.44 Hz, 1H), 7.29 (t, J=7.32 Hz,1H), 3.89 (dd, J=11.84, J₂=4.68 Hz, 1H), 3.63 (s, 3H), 2.73-2.66 (m,1H), 2.49 (m, 1H), 2.39-2.32 (m, 1H), 1.91 (m, 1H), 1.70 (br s, 1H); LCMS: ES+ 271.0.

Synthesis of6-(2,6-Bis-benzyloxy-pyridin-3-yl)-2-methyl-2,3-dihydro-isoindol-1-one(31-1)

A stirred solution of2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine25-1 (2.19 g, 5.25 mmol) and 6-bromo-2-methylisoindolin-1-one (31-1)(474 mg, 2.10 mmol) in dioxane/water (30 mL), in a sealed tube, wasdegassed for 10 minutes under an argon atmosphere. PdCl₂(dppf)-DCM (153mg, 210 μmol) was added and the reaction was heated to 80° C. for 10 h.TLC was checked in 30% ethyl acetate/hexane, which showed the completeconsumption of starting material and formation of the desired spot at rf0.4 in 30% ethylacetate-hexane. The reaction mixture was diluted withethyl acetate, washed with water. The layers were separated and theorganic layer was concentrated under reduced pressure. The crude residuewas purified using combiflash (50% ethyl acetate/hexane) andconcentrated to afford6-(2,6-Bis-benzyloxy-pyridin-3-yl)-2-methyl-2,3-dihydro-isoindol-1-one(31-1) (725 mg, 1.66 mmol, 79% yield). LC MS: ES+ 437.2.

Synthesis of3-(2-Methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-piperidine-2,6-dione(Compound 41)

A 50 ml round bottom flask was charged with6-(2,6-Bis-benzyloxy-pyridin-3-yl)-2-methyl-2,3-dihydro-isoindol-1-one(31-1) (725 mg, 1.66 mmol) and ethanol (10 mL). The resulting solutionwas degassed for 15 minutes under an argon atmosphere, palladium oncharcoal (189 mg, 178 μmol) was added and the reaction was continued for2 hrs in presence of a hydrogen balloon. TLC was checked, which showedcomplete consumption of starting material and the formation of thedesired spot at rf 0.3 in 5% MeOH-DCM. The reaction mixture was filteredthrough a celite bed and evaporated under reduced pressure. The cruderesidue was purified by flash chromatography to afford3-(2-Methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-piperidine-2,6-dione(Compound 41) (30 mg, 0.116 mmol, 7% yield) as an off-white solid. ¹HNMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.54-7.51 (m, 2H), 7.44-7.43 (m,1H), 4.44 (s, 2H), 4.01-3.99 (m, 2H), 3.07 (s, 3H), 2.72-2.67 (m, 1H),2.43 (m, 1H), 2.32-2.27 (m, 1H), 2.05 (m, 1H); LC MS: ES+ 259.4.

Synthesis of4-(2,6-bis-benzyloxy-pyridin-3-yl)-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester (32-2)

To a stirred solution of tert-butyl 5-bromoisoindoline-2-carboxylate(32-1) (300 mg, 1.00 mmol) in dioxane and water (2.5 ml), was added2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(25-1) (459 mg, 1.10 mmol) and potassium phosphate (636 mg, 3.00 mmol)at room temperature. The reaction mixture was purged with argon for 5minutes followed by addition of Pd(dppf)Cl₂-DCM (40.8 mg, 50.0 μmol) atroom temperature. The reaction mixture was heated to reflux overnight.After completion of reaction (monitored by TLC Rr=0.4 in 20% ea/hexaneand LCMS), the reaction mixture was filtered and concentrated. The cruderesidue was purified by flash column (elution with 15% EtOAc/Hexanes) toafford tert-butyl5-(2,6-bis(benzyloxy)pyridin-3-yl)isoindoline-2-carboxylate (32-2) (330mg, 648 μmol, 64.9%) as a gummy liquid. ¹H NMR (400 MHz, DMSO-d6) δ7.65-7.63 (m, 1H), 7.45-7.44 (m, 2H), 7.40-7.38 (m, 2H), 7.36-7.21 (m,7H), 7.19 (m, 1H), 6.54 (m, 1H), 5.37 (br s, 4H), 4.63-4.60 (m, 2H),4.43 (br s, 2H), 1.44-1.39 (m, 9H).

Synthesis of4-(2,6-dioxo-piperidin-3-yl)-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester (Compound 42)

To a 50 ml round bottom flask was added tert-butyl5-(2,6-bis(benzyloxy)pyridin-3-yl)isoindoline-2-carboxylate (32-2) (330mg, 648 μmol) and ethanol (10 mL). The solution was degassed for 15minutes under an argon atmosphere, palladium on charcoal (189 mg, 178μmol) was added and the reaction was continued for 2 hrs in presence ofa hydrogen balloon. TLC was checked, which showed complete consumptionof the starting material and the formation of the desired spot at if 0.3in 5% MeOH-DCM. The reaction mixture was filtered through a celite bedand evaporated under reduced pressure. The crude residue was purified byflash chromatography to afford4-(2,6-Dioxo-piperidin-3-yl)-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester (Compound 42) (186 mg, 536 μmol, 87% yield) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.87 (br s, 1H), 7.29-7.25(m, 2H), 7.11 (d, J=6.6 Hz, 1H), 4.62-4.53 (m, 4H), 3.93-3.87 (m, 1H),2.73-2.70 (m, 1H), 2.55 (m, 1H), 2.32-2.21 (m, 1H), 2.00 (br s, 1H),1.45 (s, 9H); LC MS: ES+ 331.4 (−100 and −56 mass fragment weredominant).

Synthesis of 3-(2,3-Dihydro-1H-isoindol-4-yl)-piperidine-2,6-dionehydrochloride (Compound 43)

A 25 ml round bottom flask was charged with4-(2,6-Dioxo-piperidin-3-yl)-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester Compound 42 (122 mg, 369 μmol) and 4M-Dioxane-HCl (5mL). The reaction was stirred at RT for 3h. The reaction was thenconcentrated under reduced pressure and the resulting residue wastriturated with diethyl ether to afford3-(2,3-Dihydro-1H-isoindol-4-yl)-piperidine-2,6-dione hydrochloride(Compound 43) (96 mg, 361 μmol, 98%) as an off-white solid. ¹HNMR (400MHz, DMSO-d6) δ 10.92 (s, 1H), 9.60 (br s, 2H), 7.38-7.33 (m, 2H), 7.21(d, J=7.16 Hz, 1H), 4.54 (br s, 2H), 4.46 (br s, 2H), 4.01-3.97 (m, 1H),2.71-2.67 (m, 1H), 2.58 (m, 1H), 2.32-2.26 (m, 1H), 2.00-1.98 (m, 1H);LC MS: ES+ 231.4

Synthesis of4-[2-(2,6-Dioxo-piperidin-3-yl)-acetyl]-piperazine-1-carboxylic acidtert-butyl ester (Compound 44)

A 50 ml round bottom flash was charged with2-(2,6-dioxopiperidin-3-yl)acetic acid (13-2) (200 mg, 1.16 mmol),tert-butyl piperazine-1-carboxylate (258 mg, 1.39 mmol), DIPEA (605 μL,3.48 mmol) and HATU (882 mg, 2.32 mmol) in Dimethylformamide (20 mL).The reaction was stirred at RT for 16h. The reaction was diluted withethyl acetate and washed with sat. sodium bicarbonate solution, waterand brine. The organic layer was separated, dried over sodium sulfateand concentrated under reduced pressure. The crude residue was purifiedby column chromatography eluting at 30% ethyl acetate in hexane toafford tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)acetyl)piperazine-1-carboxylate (Compound44) (145 mg, 427 μmol, 36.8%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d6) δ 10.62 (s, 1H), 3.43 (br, 4H), 3.34 (br, 2H), 3.28 (br, 2H),2.91-2.78 (m, 2H), 3.61-2.53 (m, 2H), 2.46-2.42 (m, 2H), 1.85-1.78 (brm, 2H), 1.41 (s, 9H); LC MS: ES+ 340.1.

Synthesis of 3-(2-Oxo-2-piperazin-1-yl-ethyl)-piperidine-2,6-dionehydrochloride salt (Compound 45)

A 25 ml round bottom flask was charged with tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)acetyl)piperazine-1-carboxylate (Compound44) (122 mg, 359 μmol) and 4M-Dioxane-HCl (5 mL). The reaction wasstirred at RT for 3h and then concentrated under reduced pressure andtriturated with diethyl ether to

afford 3-(2-oxo-2-(piperazin-1-yl)ethyl)piperidine-2,6-dionehydrochloride (Compound 45) (89.2 mg, 323 μmol, 90%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.15 (br, 2H), 3.69(br, 4H), 3.11-3.03 (br, d, 4H), 2.91-2.82 (m, 2H), 2.58 (m, 2H),1.85-1.78 (m, 2H); LC MS: ES+ 240.

Synthesis of 2,6-bis-benzyloxy-3-(2-methyl-1H-imidazol-4-yl)-pyridine(34-2)

A sealed tube was charge with 5-iodo-2-methyl-1H-imidazole (34-1) (100mg, 480 μmol),2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine25-1 (500 mg, 1.20 mmol) and Potassium carbonate (198 mg, 1.44 mmol) inDioxane:Water (4:1) (5 mL). The solution was degassed with argon for 10minutes. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II),complex with dichloromethane (39.1 mg, 48.0 μmol) was added to thereaction mixture and the solution was heated at 100° C. for 16h. Thereaction was cooled to RT, diluted with water, extracted with ethylacetate, washed with brine, dried over sodium sulfate and concentratedunder reduced pressure. The crude residue was purified by silica gelcolumn chromatography eluting at 30% ethyl acetate in hexane to afford2,6-bis(benzyloxy)-3-(2-methyl-1H-imidazol-5-yl)pyridine (115 mg, 309μmol, 64.6%) as an off-white solid. LC MS: ES+ 372.0

Synthesis of2,6-Bis-benzyloxy-3-(2-methyl-1-phenyl-1H-imidazol-4-yl)-pyridine (34-4)

A 25 ml round bottom flask was charged with2,6-bis(benzyloxy)-3-(2-methyl-1H-imidazol-4-yl)pyridine (34-2) (115 mg,309 μmol) and phenylboronic acid (34-3) (37.6 mg, 309 μmol) in1,2-Dichloroethene (5 mL). Pyridine (123 μL, 1.54 mmol) and copper (II)acetate monohydrate (6.16 mg, 30.9 μmol) were added to the reactionmixture and the solution was stirred at RT (keeping mouth of the RBopen) for 72h. The reaction was diluted with water, extracted with ethylacetate, washed with brine, and dried over sodium sulfate andconcentrated under reduced pressure. The crude residue was purified bysilica gel column chromatography eluting at 20% ethyl acetate in hexaneto afford2,6-bis(benzyloxy)-3-(2-methyl-1-phenyl-1H-imidazol-4-yl)pyridine (34-4)(78.0 mg, 174 μmol, 56.5%) as a gum. LC MS: ES+ 448.0

Synthesis of 3-(2-Methyl-1-phenyl-1H-imidazol-4-yl)-piperidine-2,6-dione(Compound 46)

A 25 ml round bottom flash was charged with2,6-bis(benzyloxy)-3-(2-methyl-1-phenyl-1H-imidazol-4-yl)pyridine (34-4)(75 mg, 167 μmol) and Ethanol (10 mL). The solution was degassed withargon for 10 minutes. Palladium on carbon (35.4 mg, 33.4 μmol) was addedand the reaction mixture was stirred at RT for 16h under a hydrogenballoon, filtered through celite and concentrated under reducedpressure. The crude residue was purified by column chromatographyeluting at 1.5% methanol in dichloromethane) to afford3-(2-methyl-1-phenyl-1H-imidazol-4-yl)piperidine-2,6-dione Compound 46(8.10 mg, 30.0 μmol, 18.0%) as an off-white sticky solid. ¹H NMR (400MHz, DMSO-d₆) δ 10.74 (s, 1H), 7.55-7.51 (t, J=7.64 Hz, 2H), 7.45-7.43(d, Hz, J=7.48 3H), 7.18 (s, 1H), 3.77-3.74 (t, J=7.08 Hz, 1H),2.66-2.64 (t, 1H), 2.59-2.57 (d, 1H), 2.26 (s, 3H), 2.15-2.11 (br m,2H); LC MS: ES+ 270.3

Synthesis of (1H-Indazol-3-yl)-acetic acid methyl ester (35-2)

To a stirred solution of 2-(1H-indazol-3-yl)acetic acid (35-1) (4.86 g,27.5 mmol) in Methanol (250 mL) was added sulfuric acid (0.543 g, 5.53mmol) and the reaction was refluxed at 68° C. for 16 h. Reactionprogress was monitored by TLC. The MeOH was evaporated to dryness andthe residual gum was basified with saturated sodium bicarbonate solutionand extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulphate and evaporated in vacuo to yield methyl2-(1H-indazol-3-yl)acetate (35-2) (4.90 g, 25.7 mmol, 93%) as a lightbrown solid.

Synthesis of (1-Methyl-1H-indazol-3-yl)-acetic acid methyl ester (35-3)

To a stirred solution of methyl 2-(1H-indazol-3-yl)acetate (35-2) (2.0g, 10.5 mmol) in DMF (3.0 mL) was added NaH (503 mg, 12.6 mmol) followedby the addition of MeI (1.30 mL, 21.0 mmol) at 0° C. The reactionmixture was stirred at room temperature for 1 hour, at which time TLCshowed formation of two new spots along with very little unreacted SM.The reaction was then diluted with ethyl acetate and water, the layerswere separated and the organic layer was washed with water, brine, anddried over sodium sulfate. The organics were concentrated and the crudematerial was purified by column chromatography using (100-200 silicamesh, 0%-20% ethyl acetate/hexane) to get two fractions. Analysisconfirmed the correct regiomeric structure methyl2-(1-methyl-1H-indazol-3-yl)acetate (35-3) (1.20 g, 5.87 mmol, 56.0%) asa light yellow oil. LC MS: ES+ 205.2

Synthesis of 2-(1-Methyl-1H-indazol-3-yl)-propionic acid methyl ester(35-4)

A stirred solution of methyl 2-(1-methyl-1H-indazol-3-yl)acetate (35-3)(720 mg, 3.52 mmol) in N,N-dimethylformamide (10 mL) was cooled to 0° C.and sodium hydride (168 mg, 4.22 mmol) was added in portions. Thereaction mixture was allowed to stir at room temperature for 30 minfollowed by the addition of Iodomethane (438 μL, 7.04 mmol). Thereaction mixture was stirred at room temperature for 16 h. The reactionprogress was monitored by TLC. The reaction was quenched with ice coldwater and product was extracted with ethyl acetate. The organic layerwas washed with ice cold water thrice to remove the DMF from organiclayer. The organic layer was dried over anhydrous sodium sulphate andevaporated in vacuo. The product was purified by silica gel flashchromatography (12 g Isco gold, hexane/EtOAc 0-100%) to yield methyl2-(1-methyl-1H-indazol-3-yl)propanoate (35-4) (500 mg, 2.29 mmol, 65%)as a brown oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.71 (d, J=8.2 Hz, 1H), 7.58(d, J=8.5 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 4.27(dd, J=14.4, 7.2 Hz, 1H), 3.99 (s, 3H), 3.59 (s, 3H), 1.54 (d, J=7.2 Hz,3H).

Synthesis of 4-cyano-2-methyl-2-(1-methyl-1H-indazol-3-yl)-butyric acidmethyl ester (35-5)

A stirred solution of methyl 2-(1-methyl-1H-indazol-3-yl)propanoate(35-4) (200 mg, 916 μmol) in tetrahydrofuran (10 mL) was cooled to −78°C. and Lithiumdiisopropylamide (685 μL, 1.37 mmol) was added dropwise.The reaction mixture was stirred at −78° C. for 45 minutes to generateanion, then 3-bromopropionitrile (135 μL, 1.64 mmol) was added to thereaction mixture at same temperature. The reaction mixture was broughtto room temperature and stirred for one hour. Reaction progress wasmonitored by TLC and LCMS. Reaction was quenched with saturated solutionof ammonium chloride and extraction was carried out using ethyl acetate.Organic layer was dried over anhydrous sodium sulphate and evaporated invacuo. The product was purified by silica gel flash chromatography(Column, hexane/EtOAc 0-100%) to give methyl4-cyano-2-methyl-2-(1-methyl-1H-indazol-3-yl)butanoate (35-5) (40.0 mg,147 μmol, 16.1%) as yellow gum. ES+ 272.0

Synthesis of 3-Methyl-3-(1-methyl-1H-indazol-3-yl)-piperidine-2,6-dione(Compound 47)

A stirred solution of methyl 2-(1-methyl-1H-indazol-3-yl)propanoate(35-5) (200 mg, 916 μmol) in Tetrahydrofuran (10 mL) was cooled to −78°C. and Lithiumdiisopropylamide (685 μL, 1.37 mmol) was added dropwise.The reaction mixture was stirred at −78° C. for 45 minutes to generateanion and then 3-bromopropionitrile (135 μL, 1.64 mmol) was added to thereaction mixture at the same temperature. The reaction mixture wasbrought to room temperature and stirred for one hour. Reaction progresswas monitored by TLC and LCMS. The reaction was quenched with saturatedsolution of ammonium chloride and extraction was carried out using ethylacetate. The organic layer was dried over anhydrous sodium sulphate andevaporated in vacuo. The product was purified by silica gel flashchromatography (Column, hexane/EtOAc 0-100%) to give methyl4-cyano-2-methyl-2-(1-methyl-1H-indazol-3-yl)butanoate (Compound 47)(40.0 mg, 147 μmol, 16%) as a yellow gum. ¹H NMR (400 MHz, DMSO-d₆) δ10.86 (s, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.39 (t,J=7.6 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 3.98 (s, 3H), 2.60-2.50 (m, 2H),2.43-2.39 (m, 1H), 2.15-2.12 (m, 1H), 1.66 (s, 3H). LC MS: ES+ 258.1

Synthesis of2-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazole(36-2)

To a stirred solution of 5-bromo-2-methylbenzo[d]thiazole (36-1) (0.500g, 2.19 mmol) and

4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.830 g,3.26 mmol) in dioxane (10 mL) was added potassium acetate (0.430 g, 4.38mmol) and the solution was degassed for 10 min in sealed tube.PdCl₂(dppf)-DCM (0.170 g, 208 μmol) was added and again the solution wasdegassed for 5 min and the reaction mixture was stirred at 80° C. for 3h. After the reaction was deemd complete by TLC, the reaction mixturewas diluted with ethyl acetate, washed with water and brine, the organiclayer was separated and dried over anhydrous sodium sulphate, filteredand concentrated. The crude residue was purified by columnchromatography eluted with 0 to 20% ethyl acetate in hexane to provide2-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazole(36-2) (367 mg, 1.33 mmol, 61% yield). LC MS: ES+ 276.3

Synthesis of 5-(2,6-bis-benzyloxy-pyridin-3-yl)-2-methyl-benzothiazole(36-3)

To a stirred solution of2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole(36-2) (1.1 g, 3.99 mmol) and 2,6-bis(benzyloxy)-3-bromopyridine 25-1(1.9 g, 5.13 mmol) in a sealed tube, in Dioxane (20 mL) and Water (2mL), was added K₃PO₄ (2.1 g, 9.12

mol) and the solution was degassed for 10 min. PdCl₂(dppf)-DCM (0.400 g,489 μmol) was added and again the solution was degassed for 5 min. Afterdegassing completion, the sealed tube was closed with a teflon cap andthe reaction mixture was stirred at 80° C. for 16 h. After reactioncompletion, as checked by TLC, the reaction mixture was filtered throughcelite. The organic layer was diluted with ethyl acetate, washed withwater and brine, dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography eluted with 5 to 20% ethyl acetate in hexane toprovide 5-(2,6-Bis-benzyloxy-pyridin-3-yl)-2-methyl-benzothiazole (36-3)(1.0 g, 2.28 mmol, 57% yield). LC MS: ES+ 439.3.

Synthesis of 3-(2-Methyl-benzothiazol-5-yl)-piperidine-2,6-dione(Compound 48)

To a stirred solution of5-(2,6-bis(benzyloxy)pyridin-3-yl)-2-methylbenzo[d]thiazole (36-3)(0.180 g, 410 μmol) in a mixture of Ethanol (4 mL) and THF (4 mL) wasadded Pd/C (10 wt %, 0.100 g, 943 μmol). The solution was sparged withhydrogen gas at 1 atm, RT for 16 h. After reaction completion, thereaction mixture was filtered through celite and concentrated underreduced pressure. The crude material was purified by preparative HPLC toprovide 3-(2-Methyl-benzothiazol-5-yl)-piperidine-2,6-dione (Compound48) (30 mg, 115 □mol, 28% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.87 (s,1H), 7.97 (d, J=8.1 Hz, 1H), 7.77 (s, 1H), 7.26 (d, J=7.4 Hz, 1H), 4.02(dd, J=4.4, 11.6 Hz, 1H), 2.79 (s, 3H), 2.75-2.68 (m, 1H), 2.55 (m, 1H,merged with residual solvent peak), 2.33-2.28 (m, 1H), 2.10 (m, 1H). LCMS: ES+ 261.2

Synthesis of5-(2,6-Bis-benzyloxy-pyridin-3-yl)-3-methyl-3H-benzooxazol-2-one (37-2)

To a stirred solution of compound5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (37-1) (909 mg, 3.99 mmol) and2,6-bis(benzyloxy)-3-bromopyridine 25-1 (1.9 g, 5.13 mmol), in a sealedtube in Dioxane (20 mL) and Water (2 mL), was added K₃PO₄ (2.1 g, 9.14mmol) and the solution was degassed with argon for 10 min.PdCl₂(dppf)-DCM (0.400 g, 489 μmol) was added and again the solution wasdegassed for 5 min. After degassing completion, the sealed tube wasclosed with a teflon cap and the reaction mixture stirred at 80° C. for16 h. After reaction completion as checked by TLC, the reaction mixturewas filtered through celite and the organic layer was diluted with ethylacetate, washed with water followed by brine, and dried over anhydroussodium sulphate, filtered and concentrated under reduced pressure. Thecrude residue was purified by column chromatography eluted with 5 to 20%ethyl acetate in hexane to provide5-(2,6-Bis-benzyloxy-pyridin-3-yl)-3-methyl-3H-benzooxazol-2-one (37-2)(850 mg, 1.39 mmol, 35% yield). LC MS: ES+ 439.3

Synthesis of3-(3-Methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-piperidine-2,6-dione(Compound 49)

To a stirred solution of5-(2,6-Bis-benzyloxy-pyridin-3-yl)-3-methyl-3H-benzooxazol-2-one (37-2)(850 mg, 1.93 mmol) in a mixture of Ethanol (10 mL) and THF (4 mL) wasadded Pd/C (0.100 g, 943 μmol) and and the solution was sparged withhydrogen gas at 1 atm, RT for 16 h. After reaction completion, thereaction mixture was filtered through celite and concentrated underreduced pressure. The crude residue was purified by preparative HPLC toprovide3-(3-Methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-piperidine-2,6-dione(Compound 49) (251 mg, 965 □mol, 50% yield) ¹H NMR (400 MHz, DMSO-d₆) δ10.83 (s, 1H), 7.25 (s, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz,1H), 3.90 (dd, J=4.7, 11.9 Hz, 1H), 3.40 (s, 3H, merged with residualsolvent peak), 2.68-2.64 (m, 2H), 2.27-2.24 (m, 1H), 2.02 (m, 1H). LCMS: ES-259.29

To freshly liquefied ammonia (50 ml) at −78° C. was added potassiummetal (402 mg, 10.3 mmol) (N.B. a small piece of the metal was initiallyadded to initiate the reaction, the solution turned deep blue) followedby the addition of catalytic ferric nitrate (a few crystals). Theremaining pieces of the metal were thereafter added slowly. The deepblue solution turned light greyish-brown. After stirring for 30 mins,solid powdered piperidine-2,6-dione (9-1) (500 mg, 4.42 mmol) was addedat the same temperature and the reaction mass was stirred for 1 hr. Asolution of (chloromethyl)benzene (38-1) (615 mg, 4.86 mmol) in drydiethyl ether (3 mL) was prepared and added rapidly to the mixturefollowed by stirring at −78° C. for an additional 1 hr. A sample of thereaction mixture was syringed out, ether was added, followed by theaddition of solid ammonium chloride and a few drops of 6(N) HCl (pHchecked to ensure solution acidity) and then ether was added. An aliquotof the ether layer was TLC'd (40% ethyl acetate in Hexane). Consumptionof both glutarimide as well as benzyl chloride and appearance of a newspot just above the starting material (glutarimide) was evident. GCMSmonitoring showed response of the desired mass (MS 203). The rest of thereaction mixture was quenched and worked up with ether accordingly. (Theether addition was done carefully while the ammonia from the bulkreaction mass was allowed to evaporate.) The organic extract was driedover sodium sulphate, concentrated to afford a crude residue, which waspurified by column chromatography (100-200 mesh silica gel, elution withhexane to at 20% EA/hex, compound eluted in 20% EA-hexane) to afford awhite solid, whose analysis was found to be consistent with the desiredcompound, 3-benzylpiperidine-2,6-dione (Compound 50) (120 mg, 13.3%). LCMS: ES+ 204.24, ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s, 1H), 7.29 (t,J=7.26 Hz 2H), 7.22 (d, J=7.44 Hz, 3H), 3.21 (dd, J=13.44, 3.76 Hz, 1H),2.77-2.71 (m, 1H), 2.67-2.59 (m, 1H), 2.49-2.42 (m, 2H), 1.71-1.64 (m,1H), 1.58-1.48 (m, 1H).

Synthesis of 3-Iodo-6-nitro-1H-indazole (39-2)

A solution of (39-1) (5 g, 30.6 mmol) was treated with a solution ofiodine (6.71 g, 52.9 mmol) in DMF (10 mL) and the mixture was stirred inthe presence of Potassium carbonate (8.45 g, 61.2 mmol) at roomtemperature for 2 hours. After consumption of starting material 39-1, asevident from TLC, an aqueous solution of sodium thiosulfate and water(250 mL) was added. The resulting solution was stirred for 15 min,during which time a precipitate formed. The precipitate was filtered,washed with water and dried in vacuo to afford (39-2) (7.00 g, 24.2mmol, 79%) as a light yellow solid. LCMS: ES− 287.7.

Synthesis of 3-Iodo-1-methyl-6-nitro-1H-indazole (39-3)

A stirred solution of (39-2) (4 g, 13.8 mmol) in acetone (90 mL) at 0°C. containing potassium hydroxide (1.16 g, 20.7 mmol) was treated with asolution of iodomethane (1.02 mL, 16.5 mmol) in acetone (20 mL) dropwiseand the mixture was thereafter stirred at room temperature overnight.After consumption of starting materials, as evident from TLC, thereaction mixture was partitioned between ethyl acetate and water (200mL), and the combined organic extracts were washed with brine, driedover sodium sulphate and concentrated. The crude residue was purified byflash chromatography (elution with 5-10% EtOAc-Hexane) to afford (39-3)(2.40 g, 7.91 mmol, 14.8%) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.77 (s, 1H), 8.00-7.99 (d, J=8 Hz, 1H), 7.66 (d, J=8 Hz,1H), 4.20 (s, 3H).

Synthesis of 3-(2,6-Dimethoxypyridin-3-yl)-1-methyl-6-nitro-1H-indazole(39-5)

A mixture of (39-3) (300 mg, 989 μmol), 39-4 (215 mg, 1.18 mmol) andCesium carbonate (964 mg, 2.96 mmol) in dioxane (4 mL) and water (0.5mL) was thoroughly degassed and heated at 80° C. for 12 h in presence ofPd(dppf)Cl₂-DCM (48.4 mg, 59.3 μmol). After consumption of 39-3 asevident from TLC, the mixture was filtered through a pad of Celite. Thefiltrate was partitioned between EtOAc and water, and the combinedorganic extracts were washed with brine, dried over sodium sulphate, andconcentrated. The crude residue was purified by flash chromatography(elution with 10% EtOAc-hexane) to afford (39-5) (200 mg, 636 μmol,64.5%) as a light yellow solid. LCMS: ES+ 315.1.

Synthesis of6-Hydroxy-3-(1-methyl-6-nitro-1H-indazol-3-yl)pyridin-2(3H)-one (39-6)

A stirred suspension of (39-5) (300 mg, 954 μmol) in HCl (2 mL) andacetic acid (2 mL) was heated at 140° C. in a microwave for 20 min.After consumption of 39-5 as evident from TLC, the mixture was cooled toRT and evaporated to dryness to afford (39-6) (200 mg, 698 μmol, 73.2%)as a yellow solid. LCMS: ES+ 287.2.

Synthesis of 3-(6-Amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione(Compound 51)

A stirred suspension of (39-6) (200 mg, 698 μmol) in ethanol (10 mL) atroom temperature was hydrogenated under 1 atm pressure (hydrogenballoon) in presence of palladium on carbon overnight. After formationof the desired product as evident from LCMS, the reaction mixture wasfiltered. The filtrate was concentrated to afford a crude residue whichwas purified by Preparative HPLC to afford Compound 51 (35.0 mg, 135μmol, 31.8%) as a black solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (brs,1H), 7.32 (d, J=8.64 Hz, 1H), 6.47 (d, J=8.4 Hz, 1H), 6.41 (s, 1H), 5.34(s, 2H), 4.19-4.16 (m, 1H), 3.76 (s, 3H), 2.66-2.51 (m, 2H), 2.26-2.22(m, 1H), 2.16-2.12 (m, 1H); LCMS: ES+ 259.4

Synthesis of tert-Butyl4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)piperidine-1-carboxylate(Compound 52)

A solution of Compound 51 (50 mg, 193 μmol) and tert-butyl4-oxopiperidine-1-carboxylate (46.0 mg, 231 μmol) in dichloroethane (2mL) was stirred at room temperature overnight in the presence of aceticacid (10.9 μL, 193 μmol). Sodium cyanoborohydide (24.2 mg, 386 μmol) wasadded and the stirring was continued for another 4 h. After formation ofthe desired product as evident from LCMS, the mixture was evaporated todryness, and the residue was partitioned between ethyl acetate andwater, the combined organic extracts were washed with brine, dried oversodium sulphate, and concentrated under the reduced pressure. The cruderesidue was purified by Prep HPLC to afford Compound 52 (15.0 mg, 33.9μmol, 17.6%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.81(s, 1H), 7.32 (d, J=8.68 Hz, 1H), 6.51 (d, J=9.28 Hz, 1H), 6.42 (s, 1H),5.79 (d, J=8.2 Hz, 1H), 4.20-4.14 (m, 1H), 3.91-3.85 (m, 1H), 3.81 (s,3H), 3.55-3.48 (m, 1H), 2.99-2.91 (m, 2H), 2.59-2.51 (m, 2H), 2.22-2.12(m, 2H, 1.96-1.89 (m, 2H), 1.40 (s, 9H), 1.27-1.24 (m, 2H); LC MS: ES+442.2.

Synthesis of3-(1-Methyl-6-(piperidin-4-ylamino)-1H-indazol-3-yl)piperidine-2,6-dionehydrochloride (Compound 53)

A suspension of Compound 52 (10 mg, 22.6 μmol) in ether (1 ml) wastreated with 4 M HCl in ether (0.8 mL) and the mixture was stirred at RTuntil complete consumption of starting material was evident from LCMS.The reaction mixture was thereafter concentrated and the residue wastriturated with ether, dried and finally lyophilized to afford Compound53 (8.00 mg, 21.1 μmol, 93.7%) as a white solid. 1H NMR (400 MHz,DMSO-d6) δ 10.82 (s, 1H), 8.57 (brs, 1H), 8.47 (brs, 1H), 7.32 (d,J=8.76 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 6.46 (s, 1H), 4.19 (dd, J=8.68,4.8 Hz, 1H), 3.82 (s, 3H), 3.61-3.55 (m, 1H), 3.35-3.30 (m, 2H),3.08-3.00 (m, 2H), 2.63-2.59 (m, 2H), 2.27-2.22 (m, 1H), 2.16-2.07 (m,3H), 1.62-1.56 (m, 1H); LC MS: ES+ 342.3.

Synthesis of5-(2,6-Bis-benzyloxy-pyridin-3-yl)-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester (40-2)

To a stirred solution of tert-butyl 5-bromoisoindoline-2-carboxylate(40-1) (300 mg, 1.00 mmol) in dioxane and water (2.5 ml), was added2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine25-1 (459 mg, 1.10 mmol) and potassium phosphate (636 mg, 3.00 mmol) atroom temperature. The reaction mixture was purged with argon for 5minutes followed by addition of Pd(dppf)Cl₂-DCM (40.8 mg, 50.0 μmol) atroom temperature. The reaction mixture was heating under refluxovernight. After completion of the reaction (monitored by TLC Rr=0.4 in20% ea/hexane and LCMS), the reaction mixture was filtered and theresidual crude residue was purified by a flash column (elution with 15%EtOAc/hexanes) to afford tert-butyl5-(2,6-bis(benzyloxy)pyridin-3-yl)isoindoline-2-carboxylate (40-2) (330mg, 648 μmol, 65%) as a gummy liquid. ¹H NMR (400 MHz, DMSO-d6) δ7.73-7.69 (m, 1H), 7.48-7.42 (m, 4H), 7.39-7.29 (m, 9H), 6.55 (d, J=8.08Hz, 1H), 5.40-5.36 (m, 4H), 4.59-4.57 (m, 4H), 1.46 (s, 9H).

Synthesis of5-(2,6-Dioxo-piperidin-3-yl)-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester (Compound 54)

To a stirred solution of tert-butyl5-(2,6-bis(benzyloxy)pyridin-3-yl)isoindoline-2-carboxylate (40-2) (150mg, 294 μmol) in ethanol (5 ml) was added Pd/C (31.2 mg, 29.4 μmol),followed by hydrogen balloon pressure and stirring for 4 h at r.t. AfterTLC analysis (Rf=0.3 in 50% EA/Hex) and LCMS showed product formation,the reaction mass was filtered through a celite bed, washed withmethanol and the filtrate was concentrated. The crude residue waspurified by prep TLC afforded tert-butyl5-(2,6-dioxopiperidin-3-yl)isoindoline-2-carboxylate (Compound 54) (30.0mg, 90.8 μmol, 30.8%) as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 10.83(s, 1H), 7.29-7.25 (m, 1H), 7.17 (d, J=7.24 Hz, 1H), 7.13 (d, J=7.04 Hz,1H), 4.56 (d, J=8.64 Hz, 4H), 3.89-3.82 (m, 1H), 2.69-2.61 (m, 1H),2.22-2.16 (m, 1H), 2.05-2.01 (m, 1H), 1.45 (s, 3H); LC MS: ES− 329.2.

Synthesis of 3-(Isoindolin-5-yl)piperidine-2,6-dione hydrochloride(Compound 55)

A 10 ml round bottom flask was charged with tert-butyl5-(2,6-dioxopiperidin-3-yl)isoindoline-2-carboxylate (Compound 54) (20mg, 60 μmol) and 4M-Dioxane-HCl (2 mL). The reaction was stirred at RTfor 3h. The reaction was then concentrated under reduced pressure andthe residue was triturated with diethyl ether to afford3-(isoindolin-5-yl)piperidine-2,6-dione hydrochloride (Compound 55) (14mg, 52 μmol, 86%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ10.86 (s, 1H), 9.51 (brs, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.26-7.21 (m,2H), 4.48 (s, 4H), 3.91 (dd, J=11.44, 4.36 Hz, 1H), 2.69-2.65 (m, 1H),2.48-2.43 (m, 1H), 2.22-2.18 (m, 1H), 2.01-1.99 (m, 1H); LC MS: ES+231.14.

Synthesis of 2,6-Bis-benzyloxy-[3,4′]bipyridinyl (41-2)

To the stirred solution of 2,6-bis(benzyloxy)-3-bromopyridine (16-1)(112.0 mg, 302 μmol) in Dioxane and water (7.5 mL) was addedPyridine-4-boronic acid 41-1 (42.1 mg, 453 μmol) and Potassium Phosphate(139 mg, 604 μmol). The reaction was degassed for 10 minutes andPdCl₂(dppf)-DCM (24.6 mg, 30.2 μmol) was added. The reaction wasrefluxed at 90° C. for overnight. Reaction progress was monitored byTLC. Upon completion, the reaction was diluted with water and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulphate and evaporated in vacuo. The product was purified by silica gelflash chromatography (4 g Isco gold, hexane/EtOAc 0-100%) to give2,6-bis(benzyloxy)-3,4′-bipyridine (41-2) (90.0 mg, 244 μmol, 81.0%) asa white solid. MS: ES+ 369.2.

Synthesis of 3-(Pyridin-4-yl)piperidine-2,6-dione (Compound 56)

To a solution of 2,6-bis(benzyloxy)-3,4′-bipyridine 42-2 (90 mg, 244μmol) in ethanol (5 mL) was added Pd/C (20 mg, 187 μmol) under an inertatmosphere. After stirring for 5 minutes, a hydrogen balloon wasattached to the RB flask containing the reaction mixture and thereaction mixture was stirred under a hydrogen atmosphere for 2 h. Thereaction progress was monitored by TLC (5% MeOH:DCM (0.5 Rf)). Uponcompletion, the reaction was filtered through a celite bed. The filtratewas evaporated to dryness. The product was purified by silica gel flashchromatography (4 g Isco gold, DCM/MeOH 0-10%) to give3-(pyridin-4-yl)piperidine-2,6-dione Compound 56 (25.0 mg, 131 μmol,54%). LC MS: ES-189.19. ¹H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.52(d, J=4.2 Hz, 2H), 7.28 (d, J=4.2 Hz, 2H), 3.95-3.93 (m, 1H), 2.69-2.64(m, 1H), 2.56-2.50 (m, 1H), 2.28-2.23 (m, 1H), 2.10-2.02 (m, 1H); LC MS:ES+ 191.4.

Synthesis of 4-Cyano-2-pyridin-2-yl-butyric acid ethyl ester (42-2)

To a stirred solution of methyl 2-(pyridin-2-yl)acetate (42-1) (0.500 g,3.30 mmol) in tert-butanol (10 mL) was added benzyl trimethyl ammoniumhydroxide (0.110 g, 657 μmol) dropwise in the time span of 10 minutes.After completion of the addition, the reaction mixture was stirred atroom temperature for 30 minutes followed by the addition ofacrylonitrile (0.105 g, 1.97 mmol). After addition completion, thereaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was diluted with water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crude compound was purified bycolumn chromatography using (silica, gradient, 0% to 60% ethyl acetatein hexane) to afford (42-2) (200 mg) as a gum. Yield-30%; LC MS: ES+205.1.

Synthesis of 4′,5′-Dihydro-3′H-[2,3′]bipyridinyl-2′,6′-dione (Compound57)

A solution of methyl 4-cyano-2-(pyridin-2-yl)butanoate (42-2) (200 mg,979 μmol) in Acetic acid (5 mL) and Sulphuric acid (1 mL) was stirred at110° C. for 4 hours. The reaction mixture was concentrated under reducedpressure. The crude residue was dissolved in water and its pH wasadjusted to 8 with sodium bicarbonate and extracted with ethyl acetate.The combined organic layer was washed with brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The crude masswas purified by column chromatography using (silica, gradient, 0%-5%Methanol in DCM) to afford Compound 57 (20 mg) as a solid. Yield—11%; ¹HNMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.49 (d, J=4.2 Hz, 1H), 7.78 (t,J=7.2 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.29 (t, J=11.7 Hz, 1H),4.02-4.00 (m, 1H), 2.67-2.55 (m, 2H), 2.25-2.22 (m, 1H), 2.15-2.12 (m,1H); LC MS: ES+ 191.1.

Synthesis of Isoquinoline 2-oxide (43-2)

To a stirred solution of isoquinoline (43-1) (2 g, 15.4 mmol) indichloromethane (50 mL) at 0° C., was added mCPBA (3.77 g, 16.9 mmol)portionwise and the reaction mixture was stirred at RT for 18 h. Afterconsumption of starting material as evident from TLC, the reactionmixture was quenched with a saturated solution of sodium sulphite, theorganic layer was separated and washed with a saturated solution ofsodium carbonate, brine, dried over anhydrous sodium sulphate, andconcentrated under reduced pressure to afford isoquinoline 2-oxide(43-2) (2.00 g, 13.7 mmol, 89.6%) as a white gummy solid. ¹H NMR (400MHz, DMSO-d6) δ 8.75 (s, 1H), 8.12 (d, J=6 Hz, 1H), 7.85-7.58 (m, 4H).

Synthesis of Methyl 2-(isoquinolin-1-yl)acetate (43-3)

A mixture of isoquinoline 2-oxide (43-2) (200 mg, 1.37 mmol),tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (516 mg, 2.74 mmol) andPyBroP (638 mg, 1.37 mmol) in THF (8 mL) was stirred in the presence ofDIPEA (711 μL, 4.11 mmol) at room temperature. After stirring for 2minutes, a mild exotherm was evident with considerable darkening of thesolution. After consumption of starting materials as evident from TLC,the reaction mixture was partitioned between ethyl acetate and water.The combined organic extracts were dried over sodium sulphate andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (elution with 30-40% EtOAc-Hexane) to affordmethyl 2-(isoquinolin-1-yl)acetate (43-3) (60.0 mg, 298 μmol, 21.8%) asa yellow oil. LC MS: ES+ 201.7.

Synthesis of Methyl 4-cyano-2-(isoquinolin-1-yl)butanoate (43-4)

To a stirred solution of methyl 2-(isoquinolin-1-yl)acetate (43-3) (300mg, 1.49 mmol) in THF (15 ml) was added LDA (319 mg, 2.98 mmol) at −78°.After 1h at 0° C., 3-bromo-propionitrile (199 mg, 1.49 mmol, 3 ml THF)was added to this reaction at 0° C. After 2 hour, TLC ((Rf:0.3. 5.40%ea/hex) and LCMS showed the starting material was consumed and productwas formed. The reaction mass was quenched with NH₄Cl solution,extracted with ethyl acetate, and the organic layer was dried oversodium sulphate and concentrated. The crude was purified by columnchromatography (100-200 mess silica gel) at 20% ea/hex to afford methyl4-cyano-2-(isoquinolin-1-yl)butanoate (43-4) (240 mg, 943 μmol, 63.4%)as a light yellow liquid. LC MS: ES+ 255.3.

Synthesis of 3-(Isoquinolin-1-yl)piperidine-2,6-dione (Compound 58)

A solution of methyl 4-cyano-2-(isoquinolin-1-yl)butanoate (43-4) (60mg, 235 μmol) in acetic acid (3 ml) and sulphuric acid (0.5 ml) washeated at 110° C. for 3 h. After 3 hours, TLC showed the product (Rf=0.250% ea/hex). The reaction mixture was cooled and concentrated,neutralised with bicarbonate solution, and extracted with ethyl acetate.The organic layer was washed with water, brine and dried over anhydroussodium sulphate. The crude was purified by column chromatography silicagel (100-200 mesh) eluting with 50% ea/hex to provide the desiredproduct 3-(isoquinolin-1-yl)piperidine-2,6-dione Compound 58 (15.0 mg,62.4 μmol, 26% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ10.93 (s, 1H), 8.41 (d, J=5.24 Hz, 1H), 8.31 (d, J=7.48 Hz, 1H), 8.00(d, J=7.72 Hz, 1H), 7.83-7.97 (m, 2H), 7.73-7.69 (m, 1H), 5.02 (brs,1H), 2.66-2.57 (m, 1H), 2.50-2.36 (m, 2H), 2.27-2.23 (m, 1H); LC MS: ES+241.3.

Synthesis of 3-Bromo-1-methyl-1H-pyridin-2-one (44-2)

To a stirred solution of 3-bromopyridin-2(1H)-one (44-1) (1 g, 5.74mmol) in dry DMF (4 mL) at 0° C., was added NaH (343 mg, 8.61 mmol) andthe mixture was stirred for 30 minutes followed by addition ofiodomethane (976 mg, 6.88 mmol) and stirring for another 2 h. Aftercompletion of reaction as monitored by TLC, the mixture was partitionedbetween ethyl acetate and brine. The organic extracts were dried oversodium sulfate, concentrated, and the residue was purified over silicato obtain 3-bromo-1-methylpyridin-2(1H)-one (44-2) (800 mg, 4.25 mmol,74.7%) as a solid. LC MS: ES+ 188.0.

Synthesis of1-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one(44-3)

A stirred mixture of 3-bromo-1-methylpyridin-2(1H)-one (42-2) (600 mg,3.19 mmol), bispinacolatodiboron (1.62 g, 6.38 mmol) and potassiumacetate (939 mg, 9.57 mmol) in dioxane (10 mL) was thoroughly degassedunder argon followed by addition of Pd(dppf)Cl₂-DCM (129 mg, 159 μmol)and heating at 100° C. for 5 hr. The reaction mixture was thereafterfiltered over Celite, the filtrate was evaporated and the residual crudepurified by column chromatography to obtain1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(44-3) (250 mg, 1.06 mmol, 33.3%) as a sticky mass. LCMS: calculated for[M+H]⁺ 236; found 154 (corresponding to boronic acid, [M+H]⁺ 154).

Synthesis of 2′,6′-Bis(benzyloxy)-1-methyl-[3,3′-bipyridin]-2(1H)-one(44-4)

A mixture of1-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one44-3 (200 mg, 1.30 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (16-1) (481mg, 1.30 mmol) and K₂CO₃ (539 mg, 3.90 mmol) in dioxane/H₂O (2 ml, 4:1,v/v) was thoroughly degassed under argon followed by addition ofPd₂(dba)₃ (119 mg, 130 μmol) and tri-tertiarybutylphosphinetetrafluoroborate (75.4 mg, 260 μmol) and finally heating at 100° C.overnight. The reaction mixture was filtered over Celite, the filtratewas concentrated and the crude residue was purified by flash columnchromatography to afford2′,6′-bis(benzyloxy)-1-methyl-[3,3′-bipyridin]-2(1H)-one (44-4) (120 mg,301 μmol, 23.2%). LC MS: ES+ 399.2

Synthesis of3-(1-Methyl-2-oxo-1,2-dihydropyridin-3-yl)piperidine-2,6-dione (Compound59)

To a stirred solution of2′,6′-bis(benzyloxy)-1-methyl-[3,3′-bipyridin]-2(1H)-one (44-4) (70 mg,175 μmol) in ethanol (4 ml) was added Pd/C (25 mg) and finally hydrogenballoon pressure. TLC and (Rf=0.3 in 5% MeOH/DCM) LCMS showed productformation. The reaction mass was filtered through a celite bed, whichwas subsequently washed with methanol. The filtrate was concentrated andthe crude was purified by prep TLC to afford3-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)piperidine-2,6-dione (compound59) (15 mg, 38.9%) LCMS: LC MS: ES+221.1.

Synthesis of 2-Oxo-piperidine-1,3-dicarboxylic acid 3-benzyl ester1-tert-butyl ester (45-2)

To a stirred solution of tert-butyl 2-oxopiperidine-1-carboxylate (45-1)(500 mg, 2.50 mmol) in THF (50 mL) was added Lithiumbis(trimethylsilyl)amide (5.25 mL, 5.25 mmol) at −78° C. over 30 min.After Benzyl chloroformate (712 μL, 2.50 mmol) was dissolved in THF andadded to the reaction mixture at −78° C. stirring was continued for 2hours. After the reaction mixture was quenched with aqueous saturatedNH₄Cl solution at −78° C. and extracted with EtOAc (2×100 mL), washedwith brine (50 mL), dried (Na₂SO₄) and evaporated. The crude waspurified by column chromatography (silica, gradient, 0%-20% EtOAc inHexane as eluent) to provide 3-benzyl 1-tert-butyl2-oxopiperidine-1,3-dicarboxylate (45-2) (605 mg) as a liquid.Yield—90%; LC MS: ES+ 334.3.

Synthesis of 2-Oxo-piperidine-3-carboxylic acid benzyl ester (45-3)

To a stirred solution of 3-benzyl 1-tert-butyl2-oxopiperidine-1,3-dicarboxylate (45-2) (650 mg, 1.94 mmol) in DCM (10mL) was added Trifluoroacetic acid (1.5 mL) at 0° C. The reactionmixture was stirred at 0° C. for 3 hours. The reaction mixture wasbasified with NaHCO₃ solution and extracted with EtOAc (2×50 mL), washedwith brine (50 mL), dried over Na₂SO₄ and evaporated. The crude waswashed with pentane to provide benzyl 2-oxopiperidine-3-carboxylate(45-3) (440 mg) as a brown semi-solid. Yield-97%; LC MS: ES+ 234.4.

Synthesis of 3-Hydroxy-2,6-dioxo-piperidine-3-carboxylic acid benzylester (Compound 60)

A solution of periodic acid (2.55 g, 11.2 mmol) and chromium(VI) oxide(37.5 mg, 376 μmol) in Acetonitrile (40 mL) was stirred at roomtemperature for 30 minutes. Then, Acetic anhydride (1.14 g, 11.2 mmol)was added. The reaction mixture was cooled to 0° C. and benzyl2-oxopiperidine-3-carboxylate (45-3) (440 mg, 1.88 mmol) was added inone portion and the reaction mixture was further stirred for 30 min. atroom temperature. Ice-water (15-20 mL) was added and the mixture wasextracted with ethyl acetate (3×25 mL). The combined organic layer waswashed with saturated NaHCO₃ and Na₂S₂O₃ solution, and finally withbrine. The organic phase was dried over anhydrous Na₂SO₄ and the solventwas removed under reduced pressure. The crude was purified bypreparative TLC (3% methanol—EtOAc) to provide benzyl3-hydroxy-2,6-dioxopiperidine-3-carboxylate (Compound 60) (50.0 mg) asan off-white solid. Yield-10%; ¹H NMR (400 MHz, DMSO-d6) δ 11.05 (s,1H), 7.37-7.33 (m, 5H), 6.90 (s, 1H), 5.21 (s, 2H), 2.69-2.55 (m, 1H),2.48-2.40 (m, 1H), 2.32-2.24 (m, 1H), 2.05-2.00 (m, 1H); GC MS: m/z-263.

Synthesis of N-(1-Pyridin-2-yl-ethyl)-malonamic acid ethyl ester (46-2)

To a stirred solution of 1-(pyridin-2-yl)ethanamine (46-1) (1 g, 8.18mmol) in Dichloromethane (20 mL) at 0° C. was added Triethyl amine (1.13mL, 8.18 mmol) and ethyl 3-chloro-3-oxopropanoate (1.00 mL, 8.18 mmol).The reaction was stirred at room temperature for 4 hours and thendiluted with DCM, washed with saturated sodium bicarbonate solution,water, brine and dried over sodium sulfate. The organics wereconcentrated under reduced pressure and purified by columnchromatography using (silica, gradient, 0%-2% methanol in DCM) to affordethyl 3-oxo-3-((1-(pyridin-2-yl)ethyl)amino)propanoate (46-2) (1 g) as agum. Yield-52%; LC MS: ES+ 237.3.

Synthesis of (1-Methyl-imidazo[1,5-a]pyridin-3-yl)-acetic acid ethylester (46-3)

A stirred solution of ethyl3-oxo-3-((1-(pyridin-2-yl)ethyl)amino)propanoate (46-2) (600 mg, 2.53mmol) in Phosphoryl chloride (5 mL) was heated at 100° C. for 16 hours.The reaction was concentrated under reduced pressure, diluted with icecold water, basified with saturated sodium bicarbonate solution,extracted with dichloromethane. The organics were dried over sodiumsulfate, concentrated and purified by column chromatography (silica,gradient, 0%-1.5% methanol in dichloromethane) to provide ethyl2-(1-methylimidazo[1,5-a]pyridin-3-yl)acetate (46-3) (465 mg) as a browngum. Yield-84%; LC MS: ES+ 219.1.

Synthesis of 4-Cyano-2-(1-methyl-imidazo[1,5-a]pyridin-3-yl)-butyricacid ethyl ester (46-4)

A stirred solution of ethyl2-(1-methylimidazo[1,5-a]pyridin-3-yl)acetate (46-3) (250 mg, 1.14 mmol)in Tetrahydrofuran (5 mL) under argon was cooled to −78° C. Lithiumdiisopropylamide (1.14 mL, 2.28 mmol) was added to the reaction mixturedropwise. The reaction was stirred for 1 hour at 0° C. and then onceagain cooled to −78° C. 3-Bromopropionitrile (94.1 μL, 1.14 mmol) wasadded to the reaction mixture and stirring of the mixture was continuedfor additional 30 minutes at −78° C. The reaction was gradually warmedto room temperature and stirring was continued for 3 hours. The reactionwas quenched with saturated ammonium chloride solution and extractedwith ethyl acetate. The combined organics were dried over sodium sulfateand concentrated under reduced pressure to afford ethyl4-cyano-2-(1-methylimidazo[1,5-a]pyridin-3-yl)butanoate (46-4) (180 mg)as a brown gum. Yield-58%; LC MS: ES+ 272.35.

Synthesis of3-(1-Methyl-imidazo[1,5-a]pyridin-3-yl)-piperidine-2,6-dione (Compound61)

A 10 mL round bottom flask was charged with ethyl4-cyano-2-(1-methylimidazo[1,5-a]pyridin-3-yl)butanoate (46-4) (220 mg,810 mmol), acetic acid (5 mL) and sulfuric acid (1 mL) and the reactionwas heated at 110° C. for 6h. The reaction was concentrated underreduced pressure, basified with sat'd sodium bicarbonate solution,extracted with ethyl acetate, dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography (35% ethyl acetate in hexane) to provide3-(1-methylimidazo[1,5-a]pyridin-3-yl)piperidine-2,6-dione (compound 61)(40.0 mg, 164 μmol, 20% yield) as an off-white solid. ¹H NMR (400 MHz,DMSO-d6) δ 10.92 (s, 1H), 8.10 (d, J=7.12 Hz, 1H), 7.48 (d, J=9.08 Hz,1H), 6.66-6.62 (m, 1H), 6.57 (t, J=6.62 Hz, 1H), 4.57 (dd, J=10.52, 5.0Hz, 1H), 2.72-2.62 (m, 2H), 2.46-2.36 (m, 1H), 2.22-2.14 (m, 1H); LC MS:ES+ 244.1.

Synthesis of 2,6-Dioxo-piperidine-3-carboxylic acid(2-amino-phenyl)-methyl-amide (47-2)

To a stirred solution of 2,6-dioxopiperidine-3-carboxylic acid (11-2)(220 mg, 1.4 mmol) in DMF (3.0 mL) was addedN¹-methylbenzene-1,2-diamine 47-1 (310 mg, 1.4 mmol), DIPEA (1 mL) andHATU (692 mg, 1.82 mmol). The reaction mixture was then stirred at roomtemperature for 16 hours. The reaction was diluted with ethyl acetateand the organic layer was washed with saturated aqueous NaHCO₃ solution,water, brine, dried over sodium sulfate. The reaction was concentratedand crude material was purified by Prep TLC Plate (eluting with 2%Methanol/DCM) to affordN-(2-aminophenyl)-N-methyl-2,6-dioxopiperidine-3-carboxamide (47-2) (240mg, 918 μmol, 65%) as a white solid. LC MS: ES+ 261.9.

Synthesis of 3-(1-Methyl-1H-benzoimidazol-2-yl)-piperidine-2,6-dione(Compound 62)

To a stirred solution ofN-(2-aminophenyl)-N-methyl-2,6-dioxopiperidine-3-carboxamide (47-2) (240mg, 918 μmol) was added acetic acid (3.0 mL) and the reaction wascontinued for 4 hours. The solvent in the reaction mixture wasevaporated under reduced pressure and the desired compound was purifiedby combiflash and the compound obtained was lyophilized to obtain3-(1-methyl-1H-benzo[d]imidazol-2-yl)piperidine-2,6-dione (Compound 62)(78.1 mg) as an off-white solid. Yield-35%; ¹H NMR (400 MHz, DMSO-d6) δ11.11 (s, 1H), 7.69-7.64 (m, 2H), 7.38-7.35 (m, 2H), 4.64 (m, 1H), 3.86(s, 3H), 2.69 (m, 2H), 2.52-2.50 (m, 1H), 2.30-2.26 (m, 1H); LC MS: ES+244.1.

Synthesis of 4-Cyano-2-phenyl-butyric acid ethyl ester (48-2)

To a stirred solution of ethyl 2-phenylacetate (48-1) (1.0 g, 6.09 mmol)in toluene (10.0 mL) was added Triton-B (132 μL, 304 μmol), followed byacrylonitrile (398 μL, 6.09 mmol) and the reaction mixture was stirredat room temperature for 16 hours. TLC showed formation of a new spot(Rf-0.3 in 20% ethyl acetate/hexane). The reaction was diluted withethyl acetate and the organic layer was washed with water, brine, driedover sodium sulfate and concentrated. The crude material was purified bycombiflash chromatography (0%-16% ethyl acetate/hexane) to afford ethyl4-cyano-2-phenylbutanoate (48-2) (500 mg, 2.30 mmol, 38%) as anoff-white solid. ES+ 217.0.

Synthesis of 3-Phenyl-piperidine-2,6-dione (Compound 63)

A 10 mL round bottom flask was charged with ethyl4-cyano-2-phenylbutanoate (48-2) (200 mg, 920 μmol) and Acetic acid (2mL). Sulfuric acid (0.5 mL) was added and the reaction mixture washeated at 110° C. for 6h. The reaction was concentrated under reducedpressure, basified with sat'd sodium bicarbonate solution, extractedwith ethyl acetate, dried over sodium sulfate and concentrated underreduced pressure. The crude residue was purified by columnchromatography (35% ethyl acetate in hexane) to provide3-phenylpiperidine-2,6-dione (compound 63) (27.0 mg, 142 μmol, 15.5%) asa brown solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.35-7.28 (m,2H), 7.26-7.21 (m, 3H), 3.88-3.82 (m, 1H), 2.70-2.60 (m, 1H), 2.50-2.44(m, 1H), 2.22-2.12 (m, 1H), 2.06-2.01 (m, 1H); GC MS: m/z-189.

Synthesis of 2,6-Bis-benzyloxy-3-(1H-imidazol-4-yl)-pyridine (49-2)

To a stirred solution of 4-iodo-1H-imidazole (100.0 mg, 515 μmol) inDioxane:water (4:1) (5.0 mL) was added2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(534 mg, 1.28 mmol) and K₂CO₃ (212 mg, 1.54 mmol). The reaction mixturewas degassed for 15 minutes. PdCl₂(dppf)-DCM (42.0 mg, 51.5 μmol) wasadded to the reaction mixture and the reaction mixture was heated at100° C. for 16 hours. TLC and LCMS showed formation of a new spot(Rf-0.5 in 5% Methanol/DCM). The reaction was cooled to room temperatureand filtered through a celite bed. The filtrate was separated andorganic layer was dried over sodium sulfate and concentrated. The cruderesidue was purified by column chromatography using (silica, gradient,0%-1.5% Methanol in DCM) to

afford 2,6-bis(benzyloxy)-3-(1H-imidazol-4-yl)pyridine (49-2) (125 mg,349 μmol, 67.9%) as an off-white solid. LC MS: ES+ 358.1

Synthesis of 2,6-Bis-benzyloxy-3-(1-phenyl-1H-imidazol-4-yl)-pyridine(49-3)

A 25 ml round bottom flask was charged with2,6-bis(benzyloxy)-3-(1H-imidazol-4-yl)pyridine (49-2) (125 mg, 349μmol), phenylboronic acid (42.5 ng, 349 μmol) and 1,2-Dichloroethane (5mL). Pyridine (139 μL, 1.74 mmol) and Copper(II) acetate monohydrate(6.96 mg, 34.9 μmol) were added to the reaction mixture. The reactionwas stirred at RT (keeping mouth of the RB open) for 72h. The reactionwas diluted with water, extracted with ethyl acetate, washed with brineand dried over sodium sulfate. The organics were concentrated underreduced pressure and the crude residue was purified by silica gel columnchromatography eluting at 20% ethyl acetate in hexane to

afford 2,6-bis(benzyloxy)-3-(1-phenyl-1H-imidazol-4-yl)pyridine (49-3)(80.0 mg, 184 μmol, 53%) as a gum. LC MS: ES+ 434.0

Synthesis of 3-(1-Phenyl-1H-imidazol-4-yl)-piperidine-2,6-dione(Compound 64)

A 25 ml round bottom flash was charged with2,6-bis(benzyloxy)-3-(1-phenyl-1H-imidazol-4-yl)pyridine (49-3) (75 mg,173 μmol) and Ethanol (10 mL). The solution was degassed with argon for10 minutes and then Palladium on charcoal (36.8 mg, 34.6 μmol) wasadded. The reaction was stirred at RT for 16h and then filtered throughcelite and concentrated under reduced pressure. The crude residue waspurified by column chromatography eluting at 1.5% methanol indichloromethane) to afford3-(1-phenyl-1H-imidazol-4-yl)piperidine-2,6-dione (Compound 64) (8.90mg, 34.8 μmol, 20.1%) as brown sticky solid. ¹H NMR (400 MHz, DMSO-d6) δ10.79 (s, 1H), 8.21 (s, 1H), 7.66-7.61 (m, 3H), 7.51 (t, J=7.56 Hz, 2H),7.35 (t, J=6.74 Hz, 1H), 3.85-3.82 (m, 1H), 2.67-2.58 (m, 2H), 2.15(brs, 2H); LC MS: ES+ 256.4

(S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-hydroxyoctyl)acetamide(50-2)

To a solution of(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (50-1) (450 mg, 1.12 mmol) in DMF (2.80 mL) was added8-aminooctan-1-ol (244 mg, 1.68 mmol), Diisopropylethylamine (389 μL,2.24 mmol) and HATU (509 mg, 1.34 mmol), The reaction was stirred for 24h, at which time the reaction was concentrated and purified by isco (24gcolumn 0-10% MeOH/DCM) to provide(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-hydroxypropyl)acetamide(400 mg, 67.6%). LCMS ES+=529.1

Synthesis of(S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f.][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-oxooctyl)acetamide(50-3)

A 25 mL rbf was charged with(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-hydroxyoctyl)acetamide(50-2) (400 mg, 757 μmol) and dichloromethane (4 mL). Dess-MartinPeriodinane (0.3 M in DCM, 3.02 mL, 908 μmol) was added and the reactionwas stirred at rt for 1h, then quenched with 0.5 mL isopropanol, sat'dsodium thiosulfate, and sat'd sodium bicarbonate. The reaction wasextracted 3×DCM, organics were dried over Na₂SO₄, filtered andconcentrated to provide(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-oxooctyl)acetamide(390 mg, 741 μmol, 98% yield) (50-3), which was used in subsequentreactions without further purification. LCMS ES+ 527.3.

Synthesis of(S)-8-(2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)octanoicacid (50-4)

A 25 mL rbf was charged with(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-oxooctyl)acetamide(50-3) (250 mg, 475 □mol), NaClO₂ (128 mg, 1.425 mmol), NaH₂PO₄ (202 mg,1.425 mmol), 2-methyl-2-butene (71□L, 1.425 mmol) and tert-butanol (5mL). The reaction was stirred at rt for 18h, acidified with 1N HCl andextracted with ethyl acetate. The combined organics were dried overNa₂SO₄, filtered and concentrated. The crude residue was purified byreverse-phase isco (5-100% MeCN/H₂O containing 0.01% TFA) to provide(S)-8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)octanoicacid (50-4) (200 mg, 368 □mol, 77% yield) as a white solid. LCMSES+=543.3

Synthesis of tert-Butyl(S)-(8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)octyl)carbamate(51-1)

To a solution of(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (50-1) (150 mg, 374 μmol) in DMF (935 μL) was added tert-butyl(8-aminooctyl)carbamate (118 mg, 486 μmol), Diisopropylethylamine (130L, 748 μmol) and HATU (170 mg, 448 μmol). The reaction was stirred for24 h, at which time the reaction was concentrated and purified by isco(24g column 0-10% MeOH/DCM) to provide(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-hydroxypropyl)acetamide(51-2) (200 mg, 85.4%).

Synthesis of(S)—N-(8-Aminooctyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide(51-3)

To a solution of(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-hydroxypropyl)acetamide(51-1) (200 mg, 85%) in 5 mL DCM was added TFA (3 mL). The reaction wasstirred at rt for 1h and then concentrated to provide a TFA salt of(S)—N-(8-aminooctyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide(51-2) (180 mg) which was used in subsequent reactions without furtherpurification.

(S)-8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)octanoicacid acid (50-4) (30 mg, 55.14 umol) and3-(6-amino-1-methyl-indazol-3-yl)piperidine-2,6-dione Compound 51 (15.66mg, 60.65 umol) in DMF (300 uL) were treated with HATU (39.83 mg, 104.76umol) followed by N,N-Diisopropylethylamine (32.78 mg, 253.63 umol,44.18 uL). The solution was stirred at rt. Upon completion of thereaction as determined by LCMS, the reaction was purified directly on areverse-phase C18 column, eluting with 10-100% MeCN in H₂O. The productcombining fractions were combined, solvent removed and product extracted3× CH₂Cl₂. The organic layers were dried over Na₂SO₄, filtered andsolvent removed to give8-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)octanamideDegronimer 1 (12 mg, 15.30 umol, 27.8% yield) as a light brown solid. 1HNMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.02 (s, 1H), 8.13 (t, J=5.6Hz, 1H), 8.06 (s, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.46 (d, J=8.5 Hz, 2H),7.43-7.37 (m, 2H), 4.51-4.44 (m, 1H), 4.29 (dd, J=9.5, 5.1 Hz, 1H), 3.88(s, 3H), 3.27-3.02 (m, 4H), 2.68-2.60 (m, 2H), 2.57 (s, 2H), 2.37 (s,2H), 2.35-2.29 (m, 2H), 2.20-2.09 (m, 2H), 1.60 (s, 3H), 1.48-1.40 (m,2H), 1.30 (s, 4H), 1.22 (s, 5H), 0.91 (t, J=7.4 Hz, 1H), 0.87-0.80 (m,1H). LC/MS (ES+): m/z 782.2 (M+H)⁺.

IV. Biological Data Example 7: CRBN-DDB1 Fluorescence Polarization (FP)Assay

Measuring compound ligand binding to CRBN-DDB1 was carried out using anestablished sensitive and quantitative in vitro fluorescencepolarization (FP) based binding assay. (See, I. J. Enyedy et al, J. Med.Chem., 44: 313-4324 [2001]). Compounds were dispensed from seriallydiluted DMSO stock into black 384-well compatible fluorescencepolarization plates using an Echo acoustic dispenser. Compound bindingto CRBN-DDB1 was measured by displacement of either a(−)-Thalidomide-Alexa Fluor® or Pomalidomide-fluorescein conjugatedprobe dye. A 20 μL mixture containing 400 nM CRBN-DDB 1 and 5 nM probedye in 50 mM Hepes, pH 7.4, 200 mM NaCl, 1% DMSO and 0.1% pluronicacid-127 acid was added to wells containing compound and incubated atroom temperature for 60 min. Matching control wells excluding CRBN-DDB1were used to correct for background fluorescence. Plates were read on anEnvision plate reader with appropriate FP filter sets. The corrected S(perpendicular) and P (parallel) values were used to calculatefluorescence polarization (FP) with the following equation:FP=1000*(S−G*P)/(S+G*P). The fractional amount of bound probe (FB) toCRBN-DDB1 as a function of compound concentration was fitted accordingto Wang; FEBS Letters 360, (1995), 111-114 to obtain fits for parameteroffsets and binding constant (K_(A)) of competitor compound.

Example 8: Cell Viability Analysis

RPMI 1640 medium and fetal bovine serum (FBS) were purchased from Gibco(Grand Island, N.Y., USA). CellTiter-Glo® 2.0 Assay was purchased fromPromega (Medison, Wis., USA). MOLT4.1 (WT) cell line was purchased fromATCC (Manassas, Va., USA) and MOLT4.2 (CRBN Knock Out) cell line wasgenerated in house. Cell culture flasks and 384-well microplates wereacquired from VWR (Radnor, Pa., USA).

MOLT4.1 and MOLT4.2 cell viability was determined based onquantification of ATP using CellTiter-Glo® 2.0 luminescent Assay kit,which signals the presence of metabolically-active cells. Briefly,MOLT4.1 and MOLT4.2 cells were seeded into 384-well plates at a celldensity of 750 cells per well, the plates were kept at 37° C. with 5%CO2 overnight. On the following day, test compounds were added to thecells from a top concentration of 1 μM with 10 points, half logtitration in duplicates. The cells treated in the absence of the testcompound were the negative control and the cells treated in the absenceof CellTiter-Glo® 2.0 were the positive control. At the same day ofcompound treatment, CellTiter-Glo® 2.0 was added to a plate with cellstreated in the absence of the test compound to establish Cytostaticcontrol value (Cro). Cells treated with the test compound were incubatedfor 72 hr. CellTiter-Glo reagent was then added to the cells andLuminescence was acquired on EnVision™ Multilabel Reader (PerkinElmer,Santa Clara, Calif., USA).

TABLE 1 Cmpd # Structure Kd 1

+ 2

++ 3

+ 4

++ 5

+ 6

+ 7

+ 8

++ (3:2 mixture of regioisomers) 9

++ 10

++ 11

++ 12

+++ 13

+ 14

+++ 15

++++ 16

+ 17

+ 18

+ 19

+ 20

+ 21

+++ 22

+ 23

+++ 24

++++ 25

+++ 26

+++ 27

++++ 28

+++++ 29

+++++ 30

+++++ 31

+++ 32

++++ 33

++++ 34

++++ 35

++++ 36

++++ 37

+++++ 38

+++++ 39

++++ 40

+++++ 41

++++ 42

++++ 43

45

+++ 44

+++ 46

++++ 47

++++ 48

+++++ 49

++++ 50

++++ 51

+++ 52

+++++ 53

+++++ 54

++++ 55

+++ 56

+++ 57

++++ 58

++++ 59

+++ 60

++++ 61

+++++ 62

+++ 63

++++ 64

++++ In Table 2 above >100 μM = + >30 μM = ++ 50-100 μM = +++ 10-50 μM =++++ <10 μM = +++++.

V. Representative Degronimer of the Present Invention

TABLE 2 Cmpd # Structure Kd Degro- nimer 1

+++++ In Table 2 above >100 μM = + >30 μM = ++ 50-100 μM = +++ 10-50 μM= ++++ <10 μM = +++++.

TABLE 3 Time LD50 GI50 Cell Line Sample (hr) (nM) (nM) Emax MOLT4.1Degronimer 1 72 + ++ ** MOLT4.2 Degronimer 1 72 + + * In Table 3 abovefor LD50 and GI50 >1 μM = + and 100 nM-1 μM = ++; for Emax > 50% = *0-50% = ** −50%-0% = *** and −100%-0% = ****

TABLE 4 Cell Time Emax DC50 Modification Line (hr) Sample [%] [nM]BRD4_BD1 293T.29 3 Degronimer 1 ** + In Table 4 above for DC50 > 0.83 μM= + and for Emax >50% = *

Example 9: CRBN-DDB1 Fluorescence Polarization (FP) Assay

Measuring compound ligand binding to CRBN-DDB1 was carried out using anestablished sensitive and quantitative in vitro fluorescencepolarization (FP) based binding assay. (See, I. J. Enyedy et al, J. Med.Chem., 44: 313-4324 [2001]). Compounds were dispensed from seriallydiluted DMSO stock into black 384-well compatible fluorescencepolarization plates using an Echo acoustic dispenser. Compound bindingto CRBN-DDB1 was measured by displacement of either a(−)-Thalidomide-Alexa Fluor® or Pomalidomide-fluorescein conjugatedprobe dye. A 20 μL mixture containing 400 nM CRBN-DDB 1 and 5 nM probedye in 50 mM Hepes, pH 7.4, 200 mM NaCl, 1% DMSO and 0.1% pluronicacid-127 acid was added to wells containing compound and incubated atroom temperature for 60 min. Matching control wells excluding CRBN-DDB1were used to correct for background fluorescence. Plates were read on anEnvision plate reader with appropriate FP filter sets. The corrected S(perpendicular) and P (parallel) values were used to calculatefluorescence polarization (FP) with the following equation:FP=1000*(S−G*P)/(S+G*P). The fractional amount of bound probe (FB) toCRBN-DDB1 as a function of compound concentration was fitted accordingto Wang; FEBS Letters 360, (1995), 111-114 to obtain fits for parameteroffsets and binding constant (K_(A)) of competitor compound.

Example 10: Cell Viability Analysis

RPMI 1640 medium and fetal bovine serum (FBS) were purchased from Gibco(Grand Island, N.Y., USA). CellTiter-Glo® 2.0 Assay was purchased fromPromega (Medison, Wis., USA). MOLT4.1 (WT) cell line was purchased fromATCC (Manassas, Va., USA) and MOLT4.2 (CRBN Knock Out) cell line wasgenerated in house. Cell culture flasks and 384-well microplates wereacquired from VWR (Radnor, Pa., USA).

MOLT4.1 and MOLT4.2 cell viability was determined based onquantification of ATP using CellTiter-Glo® 2.0 luminescent Assay kit,which signals the presence of metabolically-active cells. Briefly,MOLT4.1 and MOLT4.2 cells were seeded into 384-well plates at a celldensity of 750 cells per well, the plates were kept at 37° C. with 5%CO2 overnight. On the following day, test compounds were added to thecells from a top concentration of 1 μM with 10 points, half logtitration in duplicates. The cells treated in the absence of the testcompound were the negative control and the cells treated in the absenceof CellTiter-Glo® 2.0 were the positive control. At the same day ofcompound treatment, CellTiter-Glo® 2.0 was added to a plate with cellstreated in the absence of the test compound to establish Cytostaticcontrol value (CrT). Cells treated with the test compound were incubatedfor 72 hr. CellTiter-Glo reagent was then added to the cells andLuminescence was acquired on EnVision™ Multilabel Reader (PerkinElmer,Santa Clara, Calif., USA).

Example 11: HiBit Assay

Materials:

DMEM no-phenol red medium and fetal bovine serum (FBS) were purchasedfrom Gibco (Grand Island, N.Y., USA). Nano-Glo® HiBiT Lytic Assay Systemwas purchased from Promega (Medison, Wis., USA). 293T.29 (HiBiT-BRD4BD1) cell line was generated in house, ectopically expressing BRD4 BD1domain with HiBiT fusion tag. Cell culture flasks and 384-wellmicroplates were acquired from VWR (Radnor, Pa., USA).

BRD4 BD1 Degradation Analysis:

BRD4 BD1 degradation was determined based on quantification ofluminescent signal using Nano-Glo® HiBiT Lytic Assay kit. Test compoundswere added to the 384-well plate from a top concentration of 1 μM with11 points, half log titration in quadruplicates. 293T.29 cells wereadded into 384-well plates at a cell density of 15000 cells per well.The plates were kept at 37° C. with 5% CO2 for 3 hours. The cellstreated in the absence of the test compound were the negative controland the cells treated with 30 nM of a known BRD4 degrader were thepositive control. After 3-hour incubation, Nano-Glo® HiBiT Lytic Assayreagents were added to the cells. Luminescence was acquired on EnVision™Multilabel Reader (PerkinElmer, Santa Clara, Calif., USA).

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to one of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the invention as defined in the appended claims.

We claim:
 1. A Degronimer consisting of a Degron covalently linked to aTargeting Ligand, wherein the Degronimer is of Formula:

or a pharmaceutically acceptable salt or N-oxide thereof; wherein: W¹ isCR¹R², C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, or P(O)NH₂; W² is CR³R⁴, C═O, C═S,C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl,P(O)OH, or P(O)NH₂; X is independently selected from NH, NR¹², CH₂,CHR¹², C(R¹²)₂, O, or S; n is 0, 1, 2, or 3;

is a single or double bond; R⁶ is selected from:

Y is independently selected from N, CH, and CR¹¹, wherein 0, 1, 2, or 3instances of Y are selected to be N; Z is NH, O, S, or NR¹²; Z² is NH orNR¹²; R¹, R², R³, R⁴, R⁷, R⁸, and R¹⁵ are independently selected fromhydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, carbocyclic,aryl, heteroaryl, hydroxyl, halo, azide, CN—, alkoxy, amine, —NHalkyl,and —Nalkyl₂, —NH(aliphatic), and —N(aliphatic)₂; or R¹ and R² togetherwith the carbon to which they are attached form a 3-, 4-, 5-, or6-membered spiro-carbocycle, or a 4-, 5-, or 6-memberedspiro-heterocycle comprising 1 or 2 heteroatoms selected from N and O;or R³ and R⁴ together with the carbon to which they are attached form a3-, 4-, 5-, or 6-membered spiro-carbocycle, or a 4-, 5-, or 6-memberedspiro-heterocycle comprising 1 or 2 heteroatoms selected from N and O;or R⁷ and R⁸ together with the carbon to which they are attached form a3-, 4-, 5-, or 6-membered spiro-carbocycle, or a 4-, 5-, or 6-memberedspiro-heterocycle comprising 1 or 2 heteroatoms selected from N and O;or R¹ and R³ form a 1 or 2 carbon bridged ring; or R¹ and R⁷ form a 1 or2 carbon bridged ring; or R³ and R⁷ form a 1 or 2 carbon bridged ring;or R¹⁵ and R¹ form a 3, 4, 5, or 6 carbon fused ring; or R¹⁵ and R⁷ forma 3, 4, 5, or 6 carbon fused ring; or R¹⁵ and R³ form a 1 or 2 carbonbridged ring; or R¹⁵ and R⁵ form a 3, 4, 5, or 6 carbon fused ringwherein R⁵ is on the carbon alpha to R¹⁵ or a 1, 2, 3, or 4 carbonbridged ring wherein R⁵ is not on the carbon alpha to R¹⁵; R⁵ isselected at each instance from: alkyl, alkene, alkyne, aliphatic,heteroaliphatic, heterocyclic, aryl, heteroaryl, halogen, hydroxyl,alkoxy, azide, amino, —NH(aliphatic), —N(aliphatic)₂, —NHSO₂(aliphatic),—N(aliphatic)SO₂(aliphatic), —NHSO₂aryl, —N(aliphatic)SO₂aryl,—NHSO₂alkenyl, —N(aliphatic)SO₂alkenyl, —NHSO₂alkynyl,—N(aliphatic)SO₂alkynyl, and halo(aliphatic); or two R⁵ substituentstogether with the carbon atom(s) to which they are bound can form a 3,4, 5 or 6 membered ring; R¹⁰ is -Linker-Targeting Ligand; R¹¹ isselected at each instance from: hydrogen, alkyl, alkenyl, alkynyl,halogen, hydroxyl, heterocyclic, heteroalkyl, carbocyclic,heteroaliphatic, aliphatic, alkoxy, aryl, heteroaryl, alkylamino,alkylhydroxyl, —NHalkyl, —Nalkyl₂, —NH(aliphatic), —N(aliphatic)₂,amino, cyano, nitro, nitroso, sulfone, sulfoxide, thioalkyl, thiol andhaloalkyl; R¹² is selected at each instance from: hydrogen, alkyl,aliphatic, heteroaliphatic, heterocyclic, heteroaryl, aryl, —C(O)H,—C(O)OH, —C(O)alkyl, —C(O)Oalkyl, —C(O)(aliphatic, aryl,heteroaliphatic, or heteroaryl), —C(O)O(aliphatic, aryl,heteroaliphatic, or heteroaryl), alkene, and alkyne; R¹³ and R¹⁴ areindependently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy,haloalkoxy, hydroxy, amino, —NHalkyl, and —N(alkyl)₂; and or R³ and R¹⁴together with the carbon atom to which they are attached, form C(O),C(S), C═CH₂, a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-,or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selectedfrom N and O; Linker is a chemical group that covalently attaches theDegron to a Targeting Ligand; Targeting Ligand is a moiety that iscapable of binding to or binds to a Targeted Protein; and TargetedProtein is a mediator of abnormal cellular proliferation in a host inneed of such therapy.
 2. A pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically acceptable excipient.
 3. Amethod for treating a patient with abnormal cellular proliferationcomprising administering an effective amount of a compound of claim 1 ora pharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.
 4. The method of claim 3, whereinthe abnormal cellular proliferation is a cancer.
 5. The method of claim4, wherein the cancer is a solid tumor.
 6. The method of claim 4,wherein the cancer is a hematological cancer.
 7. The method of claim 3,wherein the Targeted Protein is the androgen receptor.
 8. The method ofclaim 3, wherein the Targeted Protein is the estrogen receptor.
 9. Themethod of claim 3, wherein the Targeted Protein is the epidermal growthfactor receptor.
 10. The compound of claim 1, wherein W¹ is C═O, C═S, orC═CH₂.
 11. The compound of claim 1, wherein W² is C═O, C═S, or C═CH₂.12. The compound of claim 1, wherein W¹ is C═O, W² is C═O, X is NH, andn is
 0. 13. The compound of claim 1, wherein X is NH or NR¹² wherein R¹²is alkyl.
 14. The compound of claim 1, wherein n is
 0. 15. The compoundof claim 1, wherein R⁷ and R⁸ are hydrogen.
 16. The compound of claim 1,wherein R⁶ is selected from:


17. The compound of claim 16, wherein R⁶ is


18. The compound of claim 16, wherein R⁶ is


19. The compound of claim 17, wherein W¹ is C═O, W² is C═O, X is NH, andn is
 0. 20. The compound of claim 18, wherein W¹ is C═O, W² is C═O, X isNH, and n is
 0. 21. The compound of claim 16, wherein R⁶ is selectedfrom:


22. The compound of claim 17, wherein R⁶ is selected from:


23. The compound of claim 17, wherein R⁶ is


24. The compound of claim 18, wherein R⁶ is selected from:


25. The compound of claim 1, wherein the Targeted Protein is theandrogen receptor.
 26. The compound of claim 1, wherein the TargetedProtein is the estrogen receptor.
 27. The compound of claim 1, whereinthe Targeted Protein is the epidermal growth factor receptor.
 28. Thecompound of claim 1, wherein the compound is selected from:


29. The compound of claim 1, wherein the compound is selected from:


30. The compound of claim 1, wherein Linker is selected from:

wherein: X¹ and X² are independently selected from bond: NH, NR²⁵, CH₂,CHR²⁵, C(R²⁵)₂, O, and S; R²⁰, R²¹, R²², R²³, and R²⁴ are independentlyselected from heteroarylalkyl, aryl, arylalkyl, heterocycle, aliphatic,heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolicacid, carbocycle, bond, alkyl, —C(O)— —C(O)O—, —OC(O)—, —C(O)alkyl,—C(O)Oalkyl, —C(S)—, —SO₂—, —S(O)—, —C(S)—, —C(O)NH—, —NHC(O)—,—N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-,—CH(—O—R²⁶)—, —CH(—NHR²⁵)—, —CH(—NH₂)—, —CH(—NR²⁵ ₂)—, —C(—O—R²⁶)alkyl-,—C(—NHR²⁵)alkyl-, —C(—NH₂)alkyl-, —C(—NR²⁵ ₂)alkyl-,-alkyl(R²⁷)-alkyl(R²⁸)—, —C(R²⁷R²⁸)—, —P(OXOR²⁶)O—, —P(OXOR²⁶)—,—NHC(O)NH—, —N(R²⁵)C(O)N(R²⁵)—, —N(H)C(O)N(R²⁵)—, polyethylene glycol,poly(lactic-co-glycolic acid), alkene, haloalkyl, alkoxy, and alkyne,R²⁵ is selected at each instance from alkyl, —C(O)H, —C(O)OH,—C(O)alkyl, —C(O)Oalkyl, alkenyl, and alkynyl; R²⁶ is hydrogen, alkyl,arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl,heterocyclic, aliphatic, or heteroaliphatic; and R²⁷ and R²⁸ areindependently selected from hydrogen, alkyl, amine, or together with thecarbon atom to which they are attached, form C(O), C(S), C═CH₂, a C₃-C₆spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising1 or 2 heteroatoms selected from N and O.
 31. The compound of claim 30,wherein R⁶ is selected from:


32. The compound of claim 31, wherein R⁶ is


33. The compound of claim 31, wherein R⁶ is


34. The compound of claim 32, wherein W¹ is C═O, W² is C═O, X is NH, andn is
 0. 35. The compound of claim 33, wherein W¹ is C═O, W² is C═O, X isNH, and n is
 0. 36. The compound of claim 31, wherein R⁶ is selectedfrom:


37. The compound of claim 32, wherein R⁶ is selected from:


38. The compound of claim 32, wherein R⁶ is


39. The compound of claim 33, wherein R⁶ is selected from:


40. The compound of claim 30, wherein the compound is selected from:


41. The compound of claim 30, wherein the compound is selected from: